KR20180095054A - Antitumor effect enhancer by pyrrolopyrimidine compound - Google Patents

Abstract

An antitumor effect enhancer of a compound having another antitumor effect containing a novel pyrrolopyrimidine compound is disclosed.

Description

Antitumor effect enhancer by pyrrolopyrimidine compound

(Cross reference of related application)

This application claims the benefit of Japanese Patent Application No. 2015-250705, filed on December 22, 2015, and Japanese Patent Application No. 2016-194889, filed on September 30, 2016, The specification is incorporated herein by reference in its entirety.

(Technical field)

The present invention relates to an enhancer of a compound having another antitumor effect, which contains a novel pyrrolopyrimidine compound. Further, the present invention relates to an antineoplastic agent and a pharmaceutical composition comprising a combination of a novel pyrrolopyrimidine compound and a compound having another antitumor effect.

A group of proteins called ubiquitin-like proteins (Ub1), including ubiquitin, are covalently bonded to a target protein through covalent bonding with E1, a corresponding activating enzyme, and E2, a transacting enzyme, , Stability, and intracellular localization (Non-Patent Document 1).

Ubl, Nedd8, is ATP-dependent activated by the Nedd8-specific activating enzyme APPBP1-UBA3 heterodimer (NAE). Nedd8 is then transferred to E2 (Ubc12) and is added to a set of target proteins, also called Cullin. The addition of Nedd8 to the target protein is called Neddylation. Neddylation to Cullin enhances the activity of the Cullin Ring Ligase (CRL), which functions by taking complexes with the Cullin family of proteins and adapter proteins (which can cause ubiquitin to ligase (ligase) substrates). Proteins that are ubiquitinated by CRL are degraded by proteasomes. As a substrate of CRL, many proteins which are responsible for cell cycle control such as p27, p21 and phosphorylated Iκ-B, and signal transduction in cells, and which have been reported to be degraded in tumors are known (Non-Patent Documents 2 and 3). Namely, NAE contributes to the growth and survival of tumor cells by promoting ubiquitination and proteasomal degradation of the CRL substrate protein group through activation of Nedd8.

In view of the physiological function of NAE, NAE inhibitors are characterized in that they can act simultaneously on multiple signal transduction pathways involved in the survival and proliferation of tumors. Thus, NAE inhibitors have a broad and potent anti- It is expected that it can be a drug having a tumor effect enhancing action. [(1R) -3? -Hydroxy-4? - (sulfamoyloxymethyl) cyclopentyl] -7H-1-indolecarboxamide as a compound inhibiting Nedd8 activation by NAE Pyrrolo [2,3-d] pyrimidin-4-amine (hereinafter referred to as "MLN4924") and the like are known (Patent Document 1). MLN4924 is a compound having a pyrrolopyrimidine skeleton, but has an amino group having a substituent bonded at its 4-position. It is known that accumulation of a CRL substrate protein group occurs through inhibition of Neddylation, and as a result, Apoptosis is induced (Non-Patent Document 4). Currently, MLN4924 is being developed as an antitumor agent (Patent Document 2), and in addition to the development of a single agent, a combination test with various anticancer agents is also conducted (Non-patent Documents 5 and 6). However, MLN4924 administered is pointed out to be influenced by concentration reduction in plasma to bring about the original drug effect, since most of the administered MLN4924 changes to red blood cells (Non-Patent Document 7). In addition, MLN4924 inhibits the activity of carbonic anhydrase II in that carbonic anhydrase II is expressed at a high level in normal organs such as red blood cells, kidneys, brain, eyes, and the like, Concretely, electrolyte abnormality, lowering of intraocular pressure, metabolic acidosis, polyuria, urinary stone, and sensory abnormality are concerned (Non-Patent Document 8). Accordingly, there is a need for an agent for enhancing the antitumor effect of a compound having other antitumor effect by inhibiting NAE inhibition of a new type, which has a NAE inhibitory activity and reduced carbonic anhydrase II inhibitory activity.

International Publication No. WO2006084281 International Publication No. WO2012061551

Nature Rev. Mol Cell Biol 2009 10 (5): 319-331. Genes Cancer. 20101; 1 (7): 690-699 Journal of Cellular Physiology 2000 183: 10-17 Nature. 2009 9; 458 (7239): 732-6 Mol Cancer Ther2014 13 (6); 1-11 Mol Cancer Ther2012 11 (4): 942-951 9th International ISSX Meeting Abstract P108 Israel Medical Association Journal2003: 5: APRIL: 260-263

The types of antineoplastic agents are divided into several branches and complexly classified into major groups such as alkylating agents, platinum antitumor agents, metabolic antagonists, topoisomerase inhibitors, microtubule inhibitors, anti-tumor antibiotics, and molecular targeting agents . In recent years, the combination therapy of these agents has been widely practiced rather than administering the antitumor agent alone. However, in some cases, the combination of antitumor agents may exhibit an antagonistic effect. It is unknown whether antitumor effects of these antitumor agents will be enhanced by a combination of antitumor agents. In addition, It is unpredictable to be augmented.

The inventors of the present invention have found that when a compound having a pyrrolopyrimidine skeleton is subjected to intensive studies, it has been found that a vinylene group, an ethynylene group, an arylene group, or an arylene group at the 5-position of the pyrrolopyrimidine skeleton (R ₃ in the general formula (A) (A) having a heteroarylene group,

[Expression

Is a single bond or a double bond;

X is, -O-, -CH ₂ - or -CH = a;

Y is -NH- or -O-;

R ₁ is hydrogen, fluorine, a hydroxyl group, a cyano group or an amino group;

R ₂ is hydrogen, fluorine, a hydroxyl group, a cyano group or an amino group;

R ₃ is a monocyclic or bicyclic heteroarylene group having at least one hetero atom selected from the group consisting of a vinylene group, an ethynylene group, a C6-C14 arylene group, and N, S, and O;

R ₄ is a bond, a methylene group or a C 3 -C 7 cycloalkylidene group;

R ₅ is one or have a C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O,

R ₆ represents at least one hetero atom selected from the group consisting of halogen, hydroxyl group, cyano group, C1-C6 alkyl group optionally having a phenoxy group, carbamoyl group, C1-C6 alkoxycarbonyl group, Having at least one heteroatom selected from the group consisting of N, S and O, which may have either a monocyclic or bicyclic unsaturated heterocycloalkyl group having an atom, a halogen, a hydroxyl group, a carboxyl group or a C1-C6 alkyl group as a substituent, A monocyclic or bicyclic saturated heterocycloalkyl group, an amino group, a mono- or di (C 1 -C 4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent, a halogen, a C 3 -C 7 saturated cycloalkyl group and a group consisting of N, S and O A C1-C6 alkylene group optionally having any one of a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from An alkoxy group, a benzyloxy group which may have a carbamoyl group as a substituent, a C1-C6 alkylthio group, a C1-C6 alkylsulfonyl group or an aminosulfonyl group. When a plurality of R ₆ is present, a plurality of R ₆ are may be the same or different.]

Has an excellent antitumor effect enhancing action in combination with a compound having another antitumor effect, and does not accompanied by an increase in toxicity, and has completed the invention.

Therefore, the present invention provides the following items:

Item 1. An antitumor effect enhancer of another compound having an antitumor effect, which comprises a compound represented by the above-mentioned general formula (A) or a salt thereof.

Item 2. In the general formula (A)

R ₁ is hydrogen, fluorine or hydroxyl;

R ₂ is hydrogen, fluorine or hydroxyl;

R ₃ is an ethynylene group or a monocyclic or bicyclic heteroarylene group having 1 to 4 heteroatoms selected from the group consisting of N, S and O,

An antitumor effect enhancer according to item 1.

Item 3. A compound represented by the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is hydrogen or a hydroxyl group;

R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;

R ₅ is optionally having a one or a C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O;

R ₆ is halogen; A hydroxyl group; Cyano; A C1-C6 alkyl group which may have a phenoxy group as a substituent; Carbamoyl group; A C1-C6 alkoxycarbonyl group; A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O; A monocyclic or bicyclic saturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group and a C1-C6 alkyl group; An amino group; A mono or di (C1-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent; A C1-6 alkoxy group optionally having any one of a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent; A benzyloxy group which may have a carbamoyl group as a substituent; A C1-C4 alkylthio group; A C1-C4 alkylsulfonyl group; Or aminosulfonyl group (R ₆ if a plurality is present, a plurality of R ₆ are may be the same or different.), The antitumor effect-enhancing agent according to item 1 or 2;

Item 4. A compound represented by the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is hydrogen or a hydroxyl group;

R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;

A C3-C7 saturated cycloalkyl group in which R < ₅ > may have one or more R < _{6 &} gt ;; One or a C6-C10 unsaturated cycloalkyl group which may have a plurality of R _6, or 1 or having at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group;

R ₆ is fluorine; Goat; A hydroxyl group; Cyano; A C1-C6 alkyl group which may have a phenoxy group as a substituent; Carbamoyl group; A C1-C6 alkoxycarbonyl group; A pyridinyl group optionally having at least one substituent selected from the group consisting of a halogen, a hydroxyl group and a C1-C4 alkyl group; Azetidinyl; A hydroxyazetidinyl group; A thiomorpholinyl group; A dioxydothiomorpholinyl group; A methylpiperazinyl group; A hydroxypiperidinyl group; An oxopiperidinyl group; Piperidinyl group; A hydroxypyrrolidinyl group; Oxopyrrolidinyl groups; A pyrrolidinyl group; A carboxypyrrolidinyl group; A fluoropyrrolidinyl group; A morpholinyl group; 9-oxa-3-azabicyclo [3.3.1] nonan-3-yl group; 3-oxa-8-azabicyclo [3.2.1] octan-8-yl group; An amino group; A methylamino group; Ethylamino group; Isopropylamino group; Hydroxyethylamino group; - dimethylamino group; Phenylmethylamino group; A C1-C6 alkoxy group optionally having any one of a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent; A benzyloxy group which may have a carbamoyl group as a substituent; A C1-C4 alkylthio group; A C1-C4 alkylsulfonyl group; Or aminosulfonyl group (R ₆ if a plurality is present, a plurality of R ₆ are may be the same or different.), Antitumor effect enhancer as set forth in any one of claims 1 to 3.

Item 5. A compound represented by the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is a hydroxyl group;

R ₃ is an ethynylene group;

R ₄ is a bond;

R ₅ is one or a C6-C10 which may have a plurality of R ₆ unsaturated cycloalkyl group, or one or heteroaryl of at least one member selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having an atom;

R ₆ is fluorine; Goat; A hydroxyl group; Cyano; Methyl group; A 3-fluoropyrrolidinyl group; A morpholinyl group; A thiomorpholinyl group; A 3-hydroxyazetidinyl group; Azetidinyl; An amino group; N methylamino group; A C1-C6 alkoxy group which may have either of a halogen and a C3-C7 saturated cycloalkyl group as a substituent; Or C1-C4 alkylthio group (if a plurality of R ₆ are present, the plurality of R ₆ are may be the same or different.),

An antitumor effect enhancer according to any one of items 1 to 4.

Item 6. A compound represented by the general formula (A)

Y is -NH-;

R ₁ is a hydroxyl group;

R ₂ is a hydroxyl group;

R ₃ is an ethynylene group;

R ₄ is a bond;

R ₅ is one or at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a phenyl group and a naphthyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ Lt; / RTI > is a monocyclic or bicyclic unsaturated heterocycloalkyl group;

R ₆ is fluorine; Methyl group; 3-fluoropyrrolidinyl; 3-hydroxyazetidinyl; Azetidinyl; An amino group; N-methylamino group; A C1-C6 alkoxy group optionally having a cyclopropyl group; Or C1-C4 alkylthio group (R ₆ if a plurality is present, a plurality of R ₆ are may be the same or different.), Antitumor effect enhancer as set forth in any one of claims 1 to 5.

Item 7. A compound represented by the above-mentioned general formula (A) or a salt thereof,

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 4-dihydroxy-4H-pyrrolo [ -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-fluoropyrrolidin- , 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-4,6-difluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro-4- (3- hydroxyacetidin- -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-dihydro- 4-dihydroxy-5 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine; [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-propoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-oxo-pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethylsulfanyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-6-fluoro-phenyl] -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; And

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; And salts of these compounds. The antitumor effect enhancer according to any one of items 1 to 6, wherein the antitumor effect enhancer is at least one selected from the group consisting of salts of these compounds.

8. The method according to item 8, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome modifier, a DNA damaging agent, a metabolic antagonist, The antitumor effect enhancer according to any one of items 1 to 7, which is one or more selected from the group consisting of an inhibitor, an alkylating agent, and an anthracycline antitumor agent.

9. The composition according to item 9, wherein said another antitumor effect compound is selected from the group consisting of bortezomib, carfilzomip, dixazomib, alecitin, crizotinib, apatinate, erlotinib, gefitinib, osmithinib, lapatinib, ARRY380 But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, , ABT-199, panovinostat, pravastatin, azathioprine, azelidomide, falidimide, thalidomide, KPT-330, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, borsalinostats, fluorouracil, gemcitabine, cytarabine, 6- mercaptopurine, Azathioprine, doxorubicin, xanthrone, rituximab, azaci Dean and the antitumor effect enhancer described in any one of GDC-0152, one or multiple species, wherein from 1 to 7 selected from.

Item 10. A compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7; And

Compounds having other antitumor effects

Or a pharmaceutically acceptable salt thereof.

11. The method according to item 11, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome modifier, a DNA damaging agent, a metabolic antagonist, 10. An antitumor agent according to item 10, which is one or more selected from the group consisting of an inhibitor, an alkylating agent, and an anthracycline antitumor agent.

12. The composition according to item 12, wherein the other antitumor effect compound is selected from the group consisting of bortezomib, carfilzomip, dixa zomip, alecitib, crizotinib, apatinate, erlotinib, gefitinib, osmithinib, lapatinib, ARRY380 But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, , ABT-199, panovinostat, pravastatin, azathioprine, azelidomide, falidimide, thalidomide, KPT-330, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, borsalinostats, fluorouracil, gemcitabine, cytarabine, 6- mercaptopurine, Azathioprine, doxorubicin, xanthrone, rituximab, azaci Thymine and GDC-0152, respectively.

Item 13. Use of a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 for enhancing the antitumor effect of a compound having another antitumor effect.

Item 14. The use of a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 for the preparation of an antitumor effect enhancer of a compound having another antitumor effect.

Item 15. Use of a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 for the preparation of an anti-tumor agent in combination with a compound having another antitumor effect.

16. The method according to item 16, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome modifier, a DNA damaging agent, a metabolic antagonist, The use according to any one of items 13 to 15, which is one or more selected from the group consisting of an inhibitor, an alkylating agent and an anthracycline antitumor agent.

Item 17. The use of a compound according to any one of the preceding claims, wherein the compound having the other antitumor effect is selected from the group consisting of bortezomib, carfilzomip, dixoroglom, alecitib, clitorotib, apatipinib, erlotinib, gefitinib, osmertinib, lapatinib, ARRY380 But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, , ABT-199, panovinostat, pravastatin, azathioprine, azelidomide, falidimide, thalidomide, KPT-330, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, borsalinostats, fluorouracil, gemcitabine, cytarabine, 6- mercaptopurine, Azathioprine, doxorubicin, xanthrone, rituximab, azaci Thiadiine, and GDC-0152. ≪ RTI ID = 0.0 > 15. < / RTI >

Item 18. A compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 as a combination preparation for simultaneous, sequential, or spaced use in the prevention and / , A compound having a different antitumor effect.

Item 19. A compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 for enhancing the antitumor effect of a compound having another antitumor effect.

Item 20. A pharmaceutical composition for enhancing the antitumor effect of a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 and a compound having another antitumor effect containing a pharmaceutical carrier.

Item 21. An antitumor composition comprising a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 and a compound having another antitumor effect.

22. A method for treating a tumor comprising administering to a patient a compound represented by the general formula (A) or a salt thereof according to any one of items 1 to 7 and a compound having another antitumor effect.

23. A compound having another antitumor effect, which comprises co-administering a compound represented by the general formula (A) or a salt thereof according to any one of items 1 to 7 and a compound having another antitumor effect to a patient Gt; antitumor effect of < / RTI >

Item 24. A combination of a compound represented by the general formula (A) or a salt thereof according to any one of Items 1 to 7 and a compound having another antitumor effect, for treating a tumor.

The antitumor agent containing the pyrrolopyrimidine compound represented by the above general formula (A) can be used in combination with an antitumor agent containing a compound having various other antitumor effects, Enhances the antitumor effect. Therefore, the present invention provides an antitumor effect enhancer of a compound having another antitumor effect containing the pyrrolopyrimidine compound represented by the general formula (A) as an active ingredient, the antitumor effect enhancer of the compound represented by the general formula (A) There is provided an antitumor agent comprising a combination of a pyrrolopyrimidine compound and a compound having another antitumor effect.

Therefore, the antitumor effect-enhancing agent of the compound having another antitumor effect by the pyrrolopyrimidine compound represented by the general formula (A) of the present invention and the compound represented by the general formula (A) Antitumor agents comprising a combination of compounds having an antitumor effect are very useful for the prevention and / or treatment of tumors.

1 is a graph showing the measured values of tumor volume in the control group, the reference compound administration group, the bortezomib administration group and the combination treatment group.
FIG. 2 is a graph showing the measured values of tumor volume in the control group, the reference compound administration group, the Gileterinib administration group and the combination treatment group.
3 is a graph showing the measured values of tumor volume in the control group, the reference compound administration group, the doxorubicin administration group, and the combination treatment group.
4 is a graph showing the measured values of tumor volume in the control group, the reference group compound administration group, the rituximab administration group and the combination treatment group.
5 is a graph showing the measured values of tumor volume in the control group, the reference compound administration group, the rituximab administration group and the combination treatment group.
6 is a graph showing the measured values of tumor volume in the control group, the reference compound administration group, the azacitidine administration group and the combination treatment group.

The pyrrolopyrimidine compound represented by the general formula (A) has an antitumor effect enhancing action of a compound having another antitumor effect.

In one embodiment, there is provided an antitumor effect enhancer of a compound having another antitumor effect, which comprises a compound represented by the general formula (A) or a salt thereof.

The "compound having another antitumor effect" is not limited in its form so far as it is a compound having an antitumor effect different from the compound represented by the general formula (A), and may be a low molecular compound or a salt thereof, an antibody, (Aptamers, antisense molecules, siRNA, etc.) and the like.

The functional group of the " compound having another antitumor effect " which can be used in the present invention is not particularly limited and includes kinase inhibitors, apoptosis inducers, nuclear receptor modulators, immunomodulators, extracellular export signal inhibitors, proteasome regulators, , One or more antitumor agents selected from metabolic antagonists, platinum-based antitumor agents (platinum complexes), microtubule inhibitors, alkylating agents, and anthracycline antitumor agents, and salts of the compounds .

Examples of kinase inhibitors include tyrosine kinase inhibitors and serine threonine kinase inhibitors.

Examples of tyrosine kinase inhibitors include receptor tyrosine kinase inhibitors and non-receptor tyrosine kinase inhibitors, preferably receptor tyrosine kinase inhibitors.

Examples of receptor tyrosine kinase inhibitors include ALK inhibitors, EGFR family inhibitors, FLT3 inhibitors, VEGFR inhibitors, c-kit inhibitors, or multi-kinase inhibitors that inhibit multiple receptor tyrosine kinases.

Examples of ALK inhibitors include Alectinib, Crizotinib, and the like.

EGFR family inhibitors include EGFR inhibitors and HER2 inhibitors.

Examples of EGFR inhibitors include Afatinib, Erlotinib, Gefitinib, Osimertinib (also referred to as AZD9291), and the like.

Examples of HER2 inhibitors include Lapatinib, ARRY380, and the like.

Examples of FLT3 inhibitors include Quizartinib, Gilderitinib, ASP2215, Crenolanib, and the like.

Examples of VEGFR inhibitors include, but are not limited to, Lenvatinib, Pazopanib, Sorafenib, Sunitinib, Regorafenib, and the like.

Examples of c-kit inhibitors include Masitinib and the like.

Examples of non-aqueous body tyrosine kinase inhibitors include BCR-ABL inhibitors, BTK inhibitors, and Janus kinase inhibitors (also referred to as JAK kinase inhibitors).

Examples of BCR-ABL inhibitors include Dasatinib, Imatinib, and Ponatinib.

As the BTK inhibitor, ibrutinib and the like can be mentioned.

Examples of the Janus kinase inhibitor include luxolyticin and the like.

Examples of serine threonine kinase inhibitors include PI3K inhibitors, Akt inhibitors, mTOR inhibitors, and PLK inhibitors.

Examples of PI3K inhibitors include Duvelisib, Adelalis, and the like.

Examples of AKT inhibitors include AZD5363 and MK2206.

Examples of the mTOR inhibitor include Ebelorimus and rapamycin.

Examples of PLK inhibitors include Volasertib and the like.

Examples of the apoptosis inducer include BCL-2 inhibitors and IAP antagonists.

Examples of the BCL-2 inhibitor include ABT-199 and ABT-737.

Examples of the IAP antagonist include GDC-0152 and the like.

Examples of intranuclear receptor modulators include HDAC inhibitors and steroids.

Examples of HDAC inhibitors include Panobinostat, Vorinostat (trade name Zolinda, SAHA) and the like.

Examples of steroids include Dexamethasone, Prednisolone, and the like.

Examples of immunomodulators include Lenalidomide, Pomalidomide, Thalidomide, Rituximab, and the like.

An example of an exonuclear export signal inhibitor is Exportin1 inhibitor.

An example of an inhibitor of Exportin1 is KPT-330.

Examples of proteasome modifiers include Bortezomib, Carfilzomib, Ixazomib, and the like.

Examples of DNA inhibitors include PARP inhibitors, and specifically Olaparib.

Examples of metabolic antagonists include, but are not limited to, fluorouracil, tegafur, tegafur uracil, tegafur gemelac, oteracil potassium blenders, furthuron, capecitabine, gemcitabine, cytarabine, 6-mercaptopurine, methotrexate, femetrexed, fludarabine, trifluridine, trifluridine tiphylacyl hydrochloride formulating agent, and azacitidine.

Examples of platinum-based antitumor agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, and the like.

Examples of microtubule inhibitors include vinblastine, vincristine, vinorelbine, eribulin, paclitaxel, docetaxel, albumin-suspended paclitaxel, and the like.

Examples of alkylating agents include trabepetidine, ifosfamide, vendamustine, cyclophosphamide, and dacarbazine.

Examples of the anthracycline antitumor agents include Daunorubicin, doxorubicin, and Pixantorone.

In a preferred embodiment, the compound having other antitumor effects is selected from the group consisting of bortezomib, carfilzomip, xzazomib, alecitib, clitorotib, apatipinib, erlotinib, gefitinib, osmithrinib, , ARRY380, dasatinib, imatinib, quizarthinib, gilderitinib, sunitinib, legorapenib, levatinib, parzapanib, clonolanib, masitinib, ABT-199, ABT-199, ABT-199, and ABT-199 have been used in the treatment of diabetic rheumatoid arthritis, including rheumatoid arthritis, rheumatism, rapamycin, AZD5363, MK2206, Porphyroxine, trilectidine, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, trabephenyl, Ipoh Spam Mead, Dakar Bajin, Doxorubicin, Tris, rituximab, azacytidine and GDC-0152.

among them,

From the viewpoint of exhibiting an enhancing action over a slight synergistic effect, it is preferable to use a bortezomib, carbethomipine, alecitinib, clitorotinib, apatinate, erlotinib, gepitib, lapatinib, ARRY380, imatinib, quizarthinib, Azelipramide, dexamethasone, lanalidomide, formaldehyde, fenofibrate, fenofibrate, fenofibrate, fenofibrate, fenofibrate, Amphotericin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, More preferred is phytanthrone, rituximab, azacytidine and GDC-0152,

From the viewpoint of exhibiting the enhancing action above the gentle synergistic effect, it is preferable to use the bortezomib, carfilzomip, aleitinib, apatinate, erlotinib, gefitinib, lapatinib, ARRY380, imatinib, quizarthinib, KPT-330 < / RTI > was used as an anti-inflammatory agent in the treatment and / or prophylaxis of diabetic nephropathy. Cisplatin, oxaliplatin, iopospermide, doxorubicin, pixanthrone, rituximab, azacytidine, paclitaxel, paclitaxel, GDC-0152 is more preferable,

From the viewpoint of exhibiting the enhancing action above the moderate synergistic effect, it is preferable to use the bortezomib, carfilzomip, aleitinib, apatinate, erlotinib, gefitinib, lapatinib, ARRY380, imatinib, quizarthinib, ABT-199, fluorouracil, gemcitabine, cytarabine, oxaliplatin, paclitaxel, ciprofloxacin, ciprofloxacin, ciprofloxacin, , Isofasmide, rituximab, azacytidine and GDC-0152 are more preferable,

From the viewpoint of exhibiting the enhancing action over strong synergism, lapatinib is particularly preferable.

In the present invention, "synergistic effect", "slight synergistic effect", "gentle synergistic effect", "synergistic effect", "strong synergistic effect" and " (Pharmacol Rev. 2006; 58 (3): 621-81, BMC Complement Alternative Med. 2013; 13: 212., Anticancer Res. 2005; 25 (3B): 1909 -17.). Concretely, although not particularly limited, it can be determined according to the value of the combination index (CI) as described in the first embodiment described later.

The " compound having another antitumor effect " of the present invention can be produced on the basis of a publicly known production method. Commercially available products may be used.

Each of the groups represented by the general formula (A) is specifically as follows.

In the general formula (A), the "C6-C14 arylene group" represented by R ₃ represents a monocyclic or polycyclic divalent aromatic hydrocarbon group having 6 to 14 carbon atoms. Specifically, a phenylene group, a naphthylene group, a tetrahydronaphthylene group and the like can be given, and a phenylene group and a naphthylene group are preferable.

The "monocyclic or bicyclic heteroarylene group having at least one hetero atom selected from the group consisting of N, S and O" represented by R ₃ in the general formula (A) means a group consisting of N, S and O Is a monocyclic or bicyclic heteroarylene group having from 1 to 3 at least one hetero atom selected from the group consisting of hydrogen, Specific examples thereof include a thiazolyl group, a thiazolyl group, a thiazolyl group, a thiadiazolyl group, a thiadiazolyl group, a thiadiazolyl group, a thiadiazolyl group, , Tetrazolylene group, pyridylene group, pyrazylene group, pyrimidinylene group, pyridazinylene group, indolylene group, isoindolylene group, indazololylene group, triazolopyridylene group, A thiophenylene group, a thiophenylene group, a thiophenylene group, a thienylene group, a thiophenylene group, a thiophenylene group, a thienylene group, a phenanthrene group, Dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, dihydrobenzothiophenylene group, Dioxydihydrobenzothienylene group And the like. Preferably a monocyclic heteroarylene group having at least one hetero atom selected from the group consisting of N, S and O, more preferably a monovalent heteroarylene group having at least 1 hetero atom selected from the group consisting of N, S and O A monocyclic or a 5-membered heteroarylene group having one or two hetero atoms of the species, and particularly preferably a thiazolylene group, a pyrazolylene group, an imidazolylene group, a thienylene group, and an oxazolylene group.

In the general formula (A), the "C3-C7 cycloalkylidene group" refers to a monocyclic saturated alkylidene group having 3 to 7 carbon atoms, and specifically,

. And is preferably a cyclopropylidene group.

In the present specification, the "cycloalkyl group" means a saturated or unsaturated monovalent hydrocarbon ring group. Unless otherwise specified, " cycloalkyl " includes both monocyclic and bicyclic or tricyclic rings.

In the present specification, the "heterocycloalkyl group" means a saturated or unsaturated monovalent heterocyclic group. Unless otherwise specified, " heterocycloalkyl " includes both monocyclic and bicyclic or tricyclic rings.

In the general formula (A), the "C3-C7 saturated cycloalkyl group" of the "C3-C7 saturated cycloalkyl group which may have one or more R ₆ " represented by R ₅ means a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms . Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group, and a cyclohexyl group is preferable.

In the formula (A), C6-C10 unsaturated cycloalkyl group of the "one or a C6-C10 unsaturated cycloalkyl group which may have a plurality of R ₆ 'is, having 6 to 10 carbon atoms, mono- or ring represented by R ₅ Represents an unsaturated hydrocarbon group. Specific examples include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, and a 2,3-dihydroindenyl group, and preferably a phenyl group, a naphthyl group, and a 2,3-dihydroindenyl group.

In the formula (A), R ₅ may appear, "one or a plurality of R ₆ a may be, N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of having to Cycloalkyl group "of the monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O is specifically exemplified by hexamethyleneimino group, imidazolyl group, thienyl group, A thiazolyl group, a thiazolyl group, a tetrazolyl group, a pyridyl group, a pyrazyl group, a pyrimidinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrimidinyl group, , Indolyl group, isoindolyl group, indazolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, benzofuranyl group, dihydrobenzofuranyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, Nyli, quinol An isoquinolinyl group, a quinazolinyl group, a quinoxalinyl group, a 1H-pyrazolo [4,3-b] pyridin-5-yl group, Diiodo-2H-thiochromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, 1,1-dioxo-2,3-dihydrobenzo Thiophen-7-yl group and the like. Is preferably a monocyclic or bicyclic, 5-to 10-membered unsaturated heterocycloalkyl group having 1 to 3 at least one hetero atom selected from the group consisting of N, S and O, more preferably a thienyl group, Pyrazolo [4,3-b] pyridin-5-yl group, 2,3-dihydro-1,4-benzoxazino group, 1, Diiodo-2H-thiocromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group and 1,1-dioxo-2,3-dihydrobenzo Thiophen-7-yl group.

Examples of the "halogen" represented by R ₆ in the general formula (A) include fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

In the formula (A), represented by R _6, C1-C6 alkyl group "as a substituent a C1-C6 alkyl group which may contain a phenoxy group" is, represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, specifically Includes a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- Preferably a methyl group.

In the formula (A), as the "substituent group represented by R ₆ halogen, C3-C7 saturated cycloalkyl group, and N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of A C1-C6 alkoxy group optionally having one or more groups selected from the group consisting of a methyl group, an ethyl group, a propyl group, an i-propyl group, an i- , Isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group and the like. Preferably a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.

In the formula (A), as the "substituent group represented by R ₆ halogen, C3-C7 saturated cycloalkyl group, and N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of And the "C1-C6 alkoxy group optionally having one of the cycloalkyl groups" means the above-mentioned halogen, and is preferably fluorine. The number of halogen atoms to be substituted is 1 to 3, preferably 2 or 3.

In the formula (A), as the "substituent group represented by R ₆ halogen, C3-C7 saturated cycloalkyl group, and N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of A C3-C7 saturated cycloalkyl group having 3 to 7 carbon atoms and a C1-C6 alkoxy group optionally having one of " a cycloalkyl group " is a saturated cycloalkyl group having 3 to 7 carbon atoms and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, An acyl group, and a cycloheptyl group. Preferably a cyclopropyl group. The number of substituted C3-C7 saturated cycloalkyl groups is preferably one.

In the formula (A), as the "substituent group represented by R ₆ halogen, C3-C7 saturated cycloalkyl group, and N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of C 1 -C 6 alkoxy group optionally having one or more substituents selected from the group consisting of N, S and O of the above-mentioned unsaturated heterocycloalkyl group . Is preferably a monocyclic unsaturated heterocycloalkyl group having 1 to 3 at least one hetero atom selected from the group consisting of N, S and O, more preferably at least one selected from the group consisting of N, S and O A 5-membered to 6-membered unsaturated heterocycloalkyl group having one or two heteroatoms of one kind, and particularly preferably a pyrazolyl group, a triazolyl group and a pyridyl group. The number of the unsaturated heterocycloalkyl groups to be substituted is preferably one.

In the formula (A), as the "substituent group represented by R ₆ halogen, C3-C7 saturated cycloalkyl group, and N, S and O, the group at least one of hetero atom monocyclic or 2 ring unsaturated heterocyclic having selected from the consisting of C 1 -C 6 alkoxy group which may have one of "C 1 -C 6 cycloalkyl group" is preferably a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropylmethoxy group, a 3-pyridylmethoxy group, - ylmethoxy group, ethoxy group, 2,2,2-trifluoroethoxy group, n-propoxy group and isopropoxy group.

In the general formula (A), the "benzyloxy group which may have a carbamoyl group as a substituent" represented by R ₆ is preferably a benzyloxy group and a 3-carbamoylbenzyloxy group.

In the formula (A), R ₆ to appear "as a substituent a mono or which may have a hydroxyl group or phenyl-di (C1-C4 alkyl) amino group" mono or di (C1-C4 alkyl) amino group is in the a C1- C6 alkyl group, which is monosubstituted or disubstituted by a C1-C4 alkyl group. Specific examples thereof include a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group, an isopropylamino group, a butylmethylamino group and a dimethylamino group. Preferably a methylamino group, an ethylamino group, a dimethylamino group and an isopropylamino group.

In the formula (A), represented by R ₆ as the "as a substituent a mono or di (C1-C4 alkyl) amino group which may have a hydroxyl group or phenyl group", preferably a methyl group, an ethyl group, an isopropyl group, a hydroxy Ethylamino group, dimethylamino group, and phenylmethylamino group (benzylamino group).

In the formula (A), R _6, "C1-C6 alkoxycarbonyl group" represented by is, represents a carbonyl group substituted by the above alkoxy, specifically methoxy group, ethoxy group, n- propoxy group, isopropoxy Butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, 2-methyl-butoxycarbonyl group, neopentyloxycarbonyl group, pentan-2-yloxycarbonyl group, etc., . Preferably a methoxycarbonyl group.

In the general formula (A), the "monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O" represented by R ₆ means the above-mentioned unsaturated heterocycloalkyl group And is preferably a monovalent 5-membered to 6-membered unsaturated heterocycloalkyl group having 1 to 2 heteroatoms selected from the group consisting of N, S and O, more preferably a pyridyl group .

In the formula (A), as the "substituent group represented by R _6, halogen, hydroxyl group, carboxyl group, or a C1-C6 least one heteroatom selected from the group consisting of, N, S and O, which may have any of an alkyl group Quot; monocyclic or bicyclic saturated heterocycloalkyl group having 1 to 6 hetero atoms selected from the group consisting of N, S and O " is specifically an azetidinyl group, 1-pyrrolidinyl, 4-oxo-1-piperidinyl, piperazinyl, hexamethyleneimino, morpholino, thiomorpholino, 1, Oxa-3-azabicyclo [3.3.1] nonan-3-yl group, 3-oxa-8,8-dihydroxypyrrolyl group, tetrahydrofuranyl group, tetrahydropyranyl group, - azabicyclo [3.2.1] octan-8-yl group and the like. Is preferably a monocyclic or bicyclic, 5-to 10-membered saturated heterocycloalkyl group having 1 to 4 at least one hetero atom selected from the group consisting of N, S and O, more preferably an azetidinyl group Pyrrolidinyl, piperidinyl, piperazinyl, 2-oxo-1-pyrrolidinyl, 4-oxo-1-piperidinyl, morpholino, thiomorpholino, Oxa-3-azabicyclo [3.3.1] nonan-3-yl group and 3-oxa-8-azabicyclo [3.2.1] octan-8-yl group.

In the formula (A), as the "substituent group represented by R _6, halogen, hydroxyl group, carboxyl group, or a C1-C6 least one heteroatom selected from the group consisting of, N, S and O, which may have any of an alkyl group Quot; monocyclic or bicyclic saturated heterocycloalkyl group having 1 to 6 carbon atoms " includes those exemplified above, and fluorine, chlorine and the like are preferable, and fluorine is more preferable.

In the formula (A), as the "substituent group represented by R _6, halogen, hydroxyl group, a carboxyl group and at least a heteroatom in one selected from the group, consisting of N, S and O, which may have any of a C1-C6 alkyl group C1-C6 alkyl group of a monocyclic or bicyclic saturated heterocycloalkyl group having 1 to 6 carbon atoms "includes those having 1 to 6 carbon atoms in the above-exemplified alkyl group, and is preferably a methyl group.

In the formula (A), as the "substituent group represented by R _6, halogen, hydroxyl group, a carboxyl group and at least a heteroatom in one selected from the group, consisting of N, S and O, which may have any of a C1-C6 alkyl group Is preferably an azetidinyl group, a 3-hydroxyazetidin-1-yl group, a pyrrolidinyl group, a 3-fluoropyrrolidin-1-yl group, a 3-hydroxytetrahydro- Piperidinyl group, 3-hydroxy-1-piperidinyl group, piperazin-1-yl group, 3-carboxy- Oxo-1-piperidinyl group, morpholino group, thiomorpholino group, 1,1-dioxo-thiomorpholino group, 9-oxa-3- Azabicyclo [3.3.1] nonan-3-yl group and 3-oxa-8-azabicyclo [3.2.1] octan-8-yl group.

In the formula (A), R ₆ "come C1-C6 alkyl group" represented by box, it represents an alkylthio having C1-C6 alkyl group described above, preferably C1-C4 alkylthio group, more preferably methyl Thio group and ethyl thio group.

In the formula (A), R _6, "C1-C6 alkylsulfonyl group" represented by is, represents a sulfonyl group having a C1-C6 alkyl group described above, preferably a C1-C4 alkylsulfonyl group, more preferably A methylsulfonyl group and an ethylsulfonyl group.

Y in the general formula (A) is -NH- or -O-, preferably -NH-.

In the general formula (A), R ₁ is hydrogen, fluorine, a hydroxyl group, a cyano group or an amino group, preferably hydrogen, fluorine and a hydroxyl group, more preferably a hydroxyl group.

In the general formula (A), R ₂ is hydrogen, fluorine, hydroxyl, cyano or amino, preferably hydrogen, fluorine and hydroxyl, more preferably hydrogen and hydroxyl, to be.

R ₃ in the general formula (A) is preferably a monovalent heteroarylene group having two ethynylene groups and at least one hetero atom selected from the group consisting of N, S and O, Preferably, it is an ethynylene group.

R ₄ in the general formula (A) is preferably a bond.

Formula (A) R _5, one or a C6-C10 unsaturated cycloalkyl group which may have a C3-C7 saturated cycloalkyl groups, one or a plurality of R ₆ which may have a plurality of R ₆ in the, or one Or a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O, which may have a plurality of R < ₆ >. Preferably, R ₅ is a phenyl group or naphthyl group which may be substituted with one or more R ₆ , or at least one group selected from the group consisting of N, S and O, which may have one or more R ₆ Of a monocyclic or bicyclic unsaturated heterocycloalkyl group having a hetero atom. More preferably, R ₅ is a phenyl group or an unsaturated heterocycloalkyl group which may be substituted with one or more R ₆ , more preferably R ₅ is a phenyl group which may be substituted with one or more R ₆ , Pyrazolo [4,3-b] pyridin-5-yl group, 2,3-dihydro-1,4-benzoxazino group, 1 Diiodo-2H-thiocromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, and 1,1-dioxo-2,3-di Lt; / RTI > group is a hydrobenzothiophen-7-yl group.

When R ₅ is an unsaturated heterocycloalkyl group, preferably 2,3-dihydro-1,4-benzoxazinyl, 3,4-dihydro-2H-thiochromen-8-yl, 2,3 Dihydrobenzothiophen-7-yl group and the like, and more preferably a 2,3-dihydro-1,4-benzoxazinyl group. The above-mentioned unsaturated heterocycloalkyl group may be substituted with one or more R ₆ .

When R ₅ has R ₆ , the number of R ₆ is, for example, 1 to 5, preferably 1 to 3.

When R ₅ has one or more R ₆ , R ₆ is any of the following:

(i-1) halogen,

(i-2) a hydroxyl group,

(i-3) a cyano group,

(i-4) a C1-C6 alkyl group optionally having a phenoxy group as a substituent,

(i-5) a carbamoyl group,

(i-6) a C1-C6 alkoxycarbonyl group,

(i-7) monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O,

(i-8) a monocyclic or bicyclic saturated heterocyclic group having at least one hetero atom selected from the group consisting of N, S and O, which may have a substituent selected from the group consisting of halogen, hydroxyl group, carboxyl group and C1- Alkyl group,

(i-9) amino group,

(Ci-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as the (i-10) substituent,

(i-11) which may have either of a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent A C1-6 alkoxy group,

(i-12) a benzyloxy group optionally having a carbamoyl group

(i-13) a C1-C6 alkylthio group,

(i-14) a C1-C6 alkylsulfonyl group,

(i-15) aminosulfonyl group.

R ₅ is one or a case of having a plurality of R _6, to which of the R ₆ is preferably not more than than in the formula (A):

(ii-1) halogen,

(ii-2) a hydroxyl group,

(ii-3) a cyano group,

(ii-4) a C1-C6 alkyl group optionally having a phenoxy group as a substituent,

(ii-5) carbamoyl group,

(ii-6) a C1-C6 alkoxycarbonyl group,

(ii-7) a monocyclic, 5-to 6-membered unsaturated heterocycloalkyl group having 1 to 2 at least one hetero atom selected from the group consisting of N, S and O,

(ii-8) a monocyclic or polycyclic group having 1 to 4 at least one hetero atom selected from the group consisting of N, S and O, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group and a C1- 2-membered, 5-membered to 10-membered saturated heterocycloalkyl group,

(ii-9) an amino group,

(ii-10) mono or di (C1-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent,

(ii-11) a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of halogen, C3-C7 saturated cycloalkyl group, and N, S and O as a substituent A C1-6 alkoxy group,

(ii-12) a benzyloxy group optionally having a carbamoyl group as a substituent

(ii-13) a C1-C4 alkylthio group,

(ii-14) a C1-C4 alkylsulfonyl group, or

(ii-15) an aminosulfonyl group.

R ₅ is one or a case of having a plurality of R _6, to which of the R ₆ is preferably not more than than in the formula (A):

(iii-1) Fluorine, chlorine

(iii-2) a hydroxyl group,

(iii-3) a cyano group,

(iii-4) a C1-C6 alkyl group optionally having a phenoxy group as a substituent,

(iii-5) carbamoyl group,

(iii-6) a C1-C6 alkoxycarbonyl group,

(iii-7) a 3-membered-7-membered saturated heterocycloalkyl group, especially a 5-membered-7-membered saturated heterocycloalkyl group

(iii-8) an azetidinyl group, a hydroxyazetidinyl group, a thiomorpholinyl group, a dioxydothiomorpholinyl group, a methylpiperazinyl group, a hydroxypiperidinyl group, an oxopiperidinyl group, a piperidinyl group, Oxafi-3-azabicyclo [3.3.1] nonane-1-carboxypyrrolidinyl, oxopyrrolidinyl, pyrrolidinyl, carboxylpyrrolidinyl, fluoropyrrolidinyl, morpholinyl, 3-yl group, 3-oxa-8-azabicyclo [3.2.1] octan-8-

(iii-9) an amino group,

(iii-10) a methylamino group, an ethylamino group, an isopropylamino group, a hydroxyethylamino group, a dimethylamino group, a phenylmethylamino group,

(iii-11) As the substituent, any one of halogen, C3-C7 saturated cycloalkyl group, and monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O C1-C6 alkoxy group,

(iii-12) a benzyloxy group optionally having a carbamoyl group as a substituent

(iii-13) a C1-C4 alkylthio group,

(iii-14) C1-C4 alkylsulfonyl group

(iii-15) aminosulfonyl group.

R ₅ is one or a case of having a plurality of R _6, to which of the R ₆ is preferably not more than than in the formula (A):

(iv-1) Fluorine, chlorine

(iv-2) a hydroxyl group,

(iv-3) a cyano group,

(iv-4) a methyl group,

(iv-7) 3-fluoropyrrolidinyl group, morpholinyl group, thiomorpholinyl group, 3-hydroxyazetidinyl group, azetidinyl group,

(iv-8) azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, 2-oxo-1-pyrrolidinyl group, 4-oxo-1-piperidinyl group, morpholino group, 3-azabicyclo [3.3.1] nonan-3-yl group, and 3-oxa-8-azabicyclo [3.2.1] octane- 8-Diary,

(iv-9) amino group,

(iv-10) a methylamino group,

(iv-11) a C1-C6 alkoxy group which may have either a halogen or a C3-C7 saturated cycloalkyl group as a substituent,

(iv-13) C1-C4 alkylthio group.

R ₅ is one or a case of having a plurality of R _6, to which of the R ₆ is preferably not more than than in the formula (A):

(v-1) fluorine,

(v-4) a methyl group,

(v-7) a saturated heterocycloalkyl group selected from the group consisting of 3-fluoropyrrolidinyl, 3-hydroxyazetidinyl and azetidinyl,

(v-9) amino group,

(v-10) a methylamino group,

(v-11) a C1-C6 alkoxy group optionally having a cyclopropyl group,

(v-13) C1-C4 alkylthio group.

When R ₆ is present at least a plurality, the plurality of R ₆ are may be the same or different.

The compound represented by the general formula (A) is preferably a compound having strong enzyme inhibitory activity against NAE which can be generally tested by a known method, more preferably a compound which inhibits the enzyme by 50% (IC ₅₀ Value) is 0.03 μM or less, more preferably a compound having an IC ₅₀ value of 0.01 μM or less, particularly preferably a compound having an IC ₅₀ value of 0.003 μM or less.

The compound represented by the general formula (A) is preferably a compound having a strong inhibitory activity against tumor proliferation, which can be generally tested by a known method, more preferably a compound capable of inhibiting tumor growth by 50% ₅₀ value) is 0.01 μM or less, and particularly preferably the compound has an IC ₅₀ value of 0.003 μM or less.

Furthermore, as a preferable compound, in the general formula (A), R ₁ is hydrogen, fluorine or hydroxyl group; R ₂ is hydrogen, fluorine or hydroxyl; R ₃ is an ethynylene group or a monocyclic or bicyclic heteroarylene group having 1 to 4 at least one hetero atom selected from the group consisting of N, S and O.

As a more preferable compound, in the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is hydrogen or a hydroxyl group;

R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;

R ₅ is be substituted with 1 or C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O;

R ₆ represents a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group optionally having a phenoxy group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, A monocyclic ring having at least one hetero atom selected from the group consisting of N, S and O, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group and a C 1 -C 6 alkyl group, a monocyclic or bicyclic unsaturated heterocycloalkyl group having (C1-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent, a halogen atom, a C3-C7 saturated cycloalkyl group and a group consisting of N, S and O as a substituent A C1-6 alkylene group optionally having any of monocyclic or bicyclic unsaturated heterocycloalkyl groups having at least one hetero atom selected from C1-6 If the cock group, a benzyloxy group which may a substituent group having a carbamoyl group, C1-C4 alkylthio, C1-C4 alkylsulfonyl group, or aminosulfonyl group (R ₆ is a plurality of presence, a plurality of R ₆ are the same And may be different or different).

As a more preferable compound, in the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is hydrogen or a hydroxyl group;

R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;

R ₅ is a C 3 -C 7 saturated cycloalkyl group which may have one or more R ₆ ;

One or a C6-C10 unsaturated cycloalkyl group which may have a plurality of R _6, or 1 or having at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group;

R ₆ represents a group selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, a C1-C6 alkyl group which may have a phenoxy group, a carbamoyl group, a C1-C6 alkoxycarbonyl group which may have a phenoxy group, a halogen, a hydroxyl group and a C1- A pyridinyl group, an azetidinyl group, a hydroxyazidinyl group, a thiomorpholinyl group, a dioxydothiomorpholinyl group, a methylpiperazinyl group, a hydroxypiperidinyl group, an oxopiperazine group which may have at least one selected, A saturated heterocycle selected from the group consisting of a pyridyl group, a pyridinyl group, a piperidinyl group, a hydroxypyrrolidinyl group, an oxopyrrolidinyl group, a pyrrolidinyl group, a carboxypyrrolidinyl group, a fluoropyrrolidinyl group and a morpholinyl group A substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkyl group, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a hydroxyethylamino group, a dimethylamino group, 3-yl group, 3-oxa-8-azabicyclo [3.2.1] octan-8-yl group, halogen as a substituent, a C3-C7 saturated cycloalkyl group and at least one kind selected from the group consisting of N, A C1-C6 alkylsulfinyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfinyl group, or aminosulfonyl group (if a plurality of R ₆ are present, may be a plurality of R ₆ may be the same or different.), and compounds.

As a more preferable compound, in the general formula (A)

R ₁ is a hydroxyl group;

R ₂ is a hydroxyl group;

R ₃ is an ethynylene group;

R ₄ is a bond;

R ₅ is one or a C6-C10 which may have a plurality of R ₆ unsaturated cycloalkyl group, or one or heteroaryl of at least one member selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having an atom;

Wherein R ₆ is a group selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, methyl, 3-fluoropyrrolidinyl, morpholinyl, thiomorpholinyl, 3-hydroxyazetidinyl, azetidinyl, a halogen and C3-C7 saturated cycloalkyl C1-C6 which may have any of an alkoxy group, or a C1-C4 alkylthio group (when R ₆ is a plurality is present, is a plurality of R ₆ are may be the same or different.) , And compounds.

As a more preferable compound, in the general formula (A)

Y is -NH-;

R ₁ is a hydroxyl group;

R ₂ is a hydroxyl group;

R ₃ is an ethynylene group;

R ₄ is a bond;

R ₅ is one or at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a phenyl group and a naphthyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ Lt; / RTI > is an optionally substituted monocyclic or bicyclic unsaturated heterocycloalkyl group;

R ₆ is a C1-C6 alkoxy group optionally having a fluorine, methyl group, 3-fluoropyrrolidinyl, 3-hydroxyazetidinyl, azetidinyl, amino group, methylamino group, cyclopropyl group, or C1- group (R ₆ is, it may be a plurality of R ₆ may be the same or different when a plurality of presence.), and compounds.

More preferred examples of the compound include:

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 4-dihydroxy-4H-pyrrolo [ -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-fluoropyrrolidin- , 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3-ethoxy-5-fluoro-phenyl] morpholine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-4,6-difluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-phenyl] thiomorpholine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro-4- (3- hydroxyacetidin- -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-dihydro- 4-dihydroxy-5 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine; [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-propoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6- (2,2,2-trifluoroethoxy) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [sulfamoylamino] methyl] tetrahydrofuran- [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethylsulfanyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-6-fluoro-phenyl] -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Methyl] cyclopentyl] -5- [2- (2-ethoxy-benzyl) -2,3-dihydroxy- 6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3S, 4R, 5R) -5- [4-Amino-5- [2- (2,6- difluorophenyl) ethynyl] pyrrolo [2,3- d] pyrimidin- Yl] -3,4-dihydroxy-tetrahydrofuran-2-yl] methyl sulfamate

Etc., or salts of these compounds.

More preferably,

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 4-dihydroxy-4H-pyrrolo [ -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-fluoropyrrolidin- , 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-4,6-difluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro-4- (3- hydroxyacetidin- -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-dihydro- 4-dihydroxy-5 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine; [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-propoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [sulfamoylamino] methyl] tetrahydrofuran- [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethylsulfanyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-6-fluoro-phenyl] -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;

Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

Etc., or salts of these compounds.

Next, the production method of the compound according to the present invention will be explained. The compound can be produced, for example, by the following production method or the method shown in the Reference Example. However, the production method of the compound is not limited to these reaction examples.

Recipe A

[Wherein,

Z ¹ and Z ² are the same or different and each represents hydrogen, fluorine, a hydroxyl group, an amino group, a cyano group or a protected form thereof.

P ₁ represents a protecting group of an amino group. R ₃ represents a monocyclic or bicyclic heteroarylene group having at least one hetero atom selected from the group consisting of a vinylene group, an ethynylene group, a C6-C14 arylene group, and N, S and O.

R ₄ represents a single bond, a methylene group or a C 3 -C 7 cycloalkylidene. R ₅ may be substituted with 1 or C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may be replaced by a plurality of R ₆ which may be replaced by a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O,

R ₆ is halogen; A hydroxyl group; Cyano;

A C1-C6 alkyl group which may have a phenoxy group as a substituent;

A carbamoyl group, a C1-C6 alkoxycarbonyl group;

A C4-C7 unsaturated cycloalkyl group optionally having a substituent selected from the group consisting of halogen, hydroxyl group, C1-C4 alkyl group and carbamoyl group;

A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O;

A saturated or unsaturated monocyclic or bicyclic group having at least one hetero atom selected from the group consisting of N, S, and O, which may have any of halogen, hydroxyl, oxo, carboxyl, A heterocycloalkyl group; An amino group;

A mono or di (C1-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent;

A C1-6 alkoxy group optionally having any one of a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent;

A benzyloxy group which may have a carbamoyl group as a substituent;

A C1-C4 alkylthio group;

A C1-C4 alkylsulfonyl group, or an aminosulfonyl group

.

When a plurality of R ₆ is present, a plurality of R ₆ are may be the same or different.

Represents -O-, -CH ₂ - or = CH-.]

(Step 1)

In this step, the compound represented by the general formula (1) (in the present specification, the compound represented by the general formula (1) may be simply referred to as the compound (1) ) May be simply referred to as compounds (2) to (30) in some cases) as a raw material, followed by a Mitsunobu reaction using a nitrogen nucleating agent and then deprotecting the compound (2) to be.

When Z ¹ and / or Z ² in the compound (1) represents a protective group of a hydroxyl group, examples of such a protecting group include a dimethylacetal group, a benzylidene acetal group, a benzoyl group, a tert- butyldimethylsilyloxy group, . Z ¹ and Z ² , together with the carbon atom to which they are attached,

[Wherein Ra is the same or different and represents hydrogen, methyl, ethyl, phenyl, cyclohexyl or cyclopentyl]. As the nitrogen nucleophilic agent, phthalimide is exemplified. When phthalimide is used as the nitrogen nucleating agent, the phthalimide can be used in an amount of usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole of the compound (1).

The Mitsunobu reaction can be carried out by a generally known method, for example, a method described in Synthesis, p.1 (1981), or a method similar thereto.

Examples of the azodicarboxylic acid ester used in the Mitsunobu reaction include diethyl azodicarboxylate and diisopropyl azodicarboxylate. The amount of the azodicarboxylic acid ester to be used is 1 mole of the compound (1) Is usually 1 to 10 moles, preferably 1 to 5 moles.

As the phosphine compound used in the Mitsunobu reaction method, triphenylphosphine, tributylphosphine or the like is used. The amount of the phosphine compound to be used is usually 1 to 10 moles per 1 mole of the compound (1) Preferably 1 to 5 moles.

Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 2-one can be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚. The removal of the protecting group of the nitrogen nucleating agent can be carried out by a generally known method, for example, a method described in Protective Groups in Organic Synthesis, T. Greene, John Wiley & Sons (1981) or a method similar thereto.

As a method for removing the phthalimide group, an isolated phthalimide intermediate or a Mitsunobu reaction solution can be used directly, and hydrazine, hydroxylamine, methylamine, ethylamine, n-butylamine or the like can be used as the deprotecting reagent have. The amount of the deprotecting reagent to be used is usually equimolar to excess molar relative to 1 mol of the compound (1).

Examples of the solvent include alcohols such as ethanol and methanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 2)

This step is a method for producing compound (3) by reacting compound (2) with a sulfamoylating reagent.

The sulfamoylating reagent is commercially available or can be prepared according to known methods, for example, by reacting sulfamoyl chloride, 1-aza-4- [azoniabicyclo] [2.2.2] octane- (tert-butoxycarbonyl) azanide, and the like. The sulfamoylating reagent may be used in an amount of usually 1 to 10 moles, preferably 1 to 5 moles, per 1 mole of the compound (2).

Examples of the protecting group of the amino group include a C1-C6 alkyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, and a propionyl group.

As the base, for example, triethylamine, diisopropylethylamine, pyridine, imidazole, DBU and the like can be used. When a base is used, its amount to be used is usually 1 to 30 mol, preferably 1 to 10 mol, per 1 mol of compound (2).

Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, Methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 3)

This step is a method for producing the compound (4) by using a compound (3) as a raw material and performing a coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.). The present step may be carried out in multiple stages, if necessary, and the protective reaction and the deprotection reaction may be appropriately combined.

For example, a compound in which R _{3 in the} compound (4) has an alkynylene group is obtained by using a compound (3) and a compound: HC≡CR ₄ -R ₅ (wherein R ₄ and R ₅ are as defined above) And can be obtained by coupling (Sonogashira) reaction.

In this case, the compound: HC≡CR ₄ -R ₅ (wherein R ₄ and R ₅ are as defined above) is commercially available or can be prepared according to a known method. The amount of the compound to be used is generally 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound (3).

This step can be carried out by a generally known method, for example, Chemical Reviews, Vol. 107, p. 874 (2007), and can be carried out, for example, in the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction.

Examples of the transition metal catalyst that can be used in the present process include palladium catalysts such as palladium acetate, tris (dibenzylideneacetone) dipalladium, 1,1'-bis (diphenylphosphino) ferrocene- (For example, copper iodide, copper acetate, or the like) is added to the solution in the presence of a ligand (e.g. triphenylphosphine, tri-tert-butylphosphine, etc.) It is used as a catalyst. The amount of the transition metal catalyst to be used varies depending on the kind of the catalyst. For example, the amount of the transition metal catalyst to be used is generally 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of the compound (4). The amount of the ligand to be used is generally 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound (4). The amount of the cocatalyst to be used is generally 0.0001 to 4 mol, preferably 0.001 to 2 mol, per 1 mol of the compound (4).

The reaction may be carried out in the presence of a base. Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide , Organic bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyllithium, or organic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride and the like Base. Among them, organic bases such as triethylamine and diisopropylethylamine are preferable. The amount of the base to be used is generally 0.1 to 50 mol, preferably 1 to 20 mol, per 1 mol of the compound (4).

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples of the solvent include hydrocarbons (e.g., benzene, toluene, xylene and the like), nitriles (e.g., acetonitrile and the like), ethers (e.g., dimethoxyethane, tetrahydrofuran, Dioxane and the like), alcohols (for example, methanol and ethanol), aprotic polar solvents (for example, dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide), water and mixtures thereof. The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is usually from 0 ° C to the boiling point of the solvent, preferably from 0 to 150 ° C.

This step is also an organic boron compound having a compound (3) and a substituent -R ₃ -R ₄ -R ₅ (wherein R ₃ , R ₄ and R ₅ are as defined above) (boric acid compound, boric acid Ester, etc.), and can also be obtained by Suzuki-Miyaura coupling.

In this case, the organic boron compound is commercially available or can be produced in accordance with a known method. The amount of the organoboron compound to be used is usually 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound (3).

In this case, Suzuki-Miyaura coupling may be carried out by a commonly known method, for example, Chemical Reviews, Vol. 95, p. 2457 (1995) or a method analogous thereto.

Examples of the reaction catalyst used in the Suzuki-Miyaura coupling include tetrakis triphenylphosphine palladium (0), bis (triphenylphosphine) palladium (II) dichloride, 1,1'-bis Phenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, and the like. The amount of the reaction catalyst used varies depending on the kind of the catalyst. The amount of the catalyst to be used is generally 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of the compound (3).

Examples of the solvent include hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile and the like, ethers such as dimethoxyethane, tetrahydrofuran, 1 , 4-dioxane and the like), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., dimethylformamide and dimethyl sulfoxide), water and the like. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 4)

This step is a method for producing the compound (5) by deprotecting the amino group protection of the compound (4). The deprotection can be carried out by a generally known method, for example, a method described in Protective Groups in Organic Synthesis, T. Greene, John Wiley & Sons (1981) or a method similar thereto. As the protecting group, tert-butyloxycarbonyl is exemplified. When a tert-butyloxycarbonyl group is used as the protecting group, deprotection under acidic conditions is preferable. Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, and tosyl acid. The amount of the acid to be used is preferably 1 to 100 mol based on 1 mol of the compound (4).

The solvent to be used in the reaction may be any solvent which does not adversely affect the reaction and includes, for example, alcohols such as methanol and the like, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as (E.g., methylene chloride, chloroform, and 1,2-dichloroethane), nitriles (e.g., acetonitrile and the like), ethers (e.g., dimethoxyethane, tetrahydrofuran, Polar solvents (for example, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) or mixtures thereof are used. The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is usually 0 to 120 ° C, preferably 0 to 90 ° C.

The compound (1) used as a raw material in the production method A is commercially available or can be produced in accordance with a known method. For example, the compound (7) wherein Z ¹ and Z ² in the general formula (1) are hydroxyl-specific protecting groups can be produced by the following production process B.

Recipe B

Wherein Ra is the same or different and represents hydrogen, methyl, ethyl, phenyl, cyclohexyl or cyclopentyl.

(Step 5)

This step is a method for producing Compound (7) by protecting two of the hydroxyl groups of Compound (6). Examples of the protecting reagent include a dialkoxyalkane and the like. The protecting reagent may be used usually in an amount of 1 to 100 moles, preferably 1 to 10 moles, per 1 mole of the compound (6).

The protection can be carried out by a generally known method, for example, a method described in Protective Groups in Organic Synthesis, T. W. G. reene, John Wiley & Sons (1981), or a method similar thereto.

As the reaction catalyst, for example, p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonate, perchloric acid, sulfuric acid and the like can be used. When a reaction catalyst is used, the amount thereof to be used differs depending on the kind of the catalyst. For example, generally 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of the compound (6).

Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, Amide, N-methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

Further, the compound (15) wherein Z ¹ and Z ² in the general formula (1) are protected with a specific hydroxyl group can also be produced by the following production process C.

Recipe C

Wherein P ₂ represents a protecting group of a hydroxyl group. Ra is the same as above.]

(Step 6)

This step is a method for producing Compound (9) by protecting two of the hydroxyl groups of Compound (8). This protection reaction can be carried out by the same method as in Step 5.

(Step 7)

The present step is to prepare an isomeric mixture of the pyrrolopyrimidine compound (10) by reacting an isomeric mixture of the compound (9) and 2- (4,6-dichloropyrimidin-5-yl) acetaldehyde in the presence of a base Method.

The 2- (4,6-dichloropyrimidin-5-yl) acetaldehyde can be used usually in an amount of 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound (9).

This reaction can be carried out by a generally known method, for example, a method described in Tetrahedron Letters, 26 (16), 2001-2 (1985), or a method similar thereto.

As the base, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, DBU and the like can be used. When a base is used, its amount to be used is usually 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of compound (9).

Examples of the solvent include alcohols such as ethanol, 2-propanol, 2-butanol, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, , N-methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 8)

This step is a method of converging an isomeric mixture of the compound (10) to the isomeric compound (11) in the presence of an acid catalyst.

As the acid, for example, p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonate, perchloric acid, sulfuric acid and the like can be used. The amount to be used is usually 0.001 to 10 mol, preferably 0.01 to 2 mol, per 1 mol of compound (10).

Examples of the solvent include acetone, 2-butanone, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide , N, N-dimethylacetamide and N-methylpyrrolidin-2-one can be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 1 to 48 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 9)

This step is a method for protecting the hydroxyl group of the compound (11) using a compound P ₂ -Cl (wherein P ₂ represents a protecting group of a hydroxyl group).

This reaction can be carried out by a generally known method, for example, a method described in Protective Groups in Organic Synthesis, T. Greene, John Wiley & Sons (1981) or a method similar thereto.

In the compound P ₂ -C ₁ , the protecting group of the hydroxyl group represented by P ₂ is not particularly limited as long as it has the function, and examples thereof include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl; Lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; Lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; For example, a tetrahydropyranyl group; For example, a trimethylsilylethoxymethyl group; An aralkyl group such as benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group and trityl group; Examples thereof include an acyl group such as a formyl group, an acetyl group and a trifluoroacetyl group, and particularly preferably a methyl group, a methoxymethyl group, a tetrahydropyranyl group, a trimethylsilylethoxymethyl group, a tert-butyldimethylsilyl group, Group and the like are preferable.

The compound is commercially available or can be prepared according to known methods. The compound can be used usually in an amount of 1 to 20 moles, preferably 1 to 5 moles, per 1 mole of the compound (11).

As the base, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, DBU and the like can be used. The amount to be used is usually 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of the compound (11).

Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, Methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 10)

This step is a step of reacting compound (12) with iodosuccinimide to introduce an iodine atom to prepare compound (13).

As a method of iodination, it can be produced by a method described in International Publication WO2006 / 102079 pamphlet, or a method similar to these methods. The iodosuccinimide can be used usually in an amount of 1 to 20 moles, preferably 1 to 5 moles, per 1 mole of the compound (12).

As the solvent, acetone, acetonitrile, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, Acetamide, N-methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 11)

This step is a step of preparing Compound (14) by deprotecting the protection of the hydroxyl group of Compound (13).

The deprotection can be carried out by a generally known method, for example, a method described in Protective Groups in Organic Synthesis, T. W. G. reene, John Wiley & Sons (1981), or a method similar thereto.

When a tert-butyldimethylsilyl group is used as the protecting group, tetrabutylammonium fluoride can be mentioned as the deprotecting reagent. The amount of the reagent to be used is preferably 1 to 10 moles relative to 1 mole of the compound (13).

The solvent to be used in the reaction may be any solvent that does not adversely affect the reaction, and examples thereof include ethers (e.g., 1,2-dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents , N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorylamide, etc.) or a mixture thereof is used. The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is usually 0 to 80 캜, preferably 0 to 50 캜.

(Step 12)

This step is a method for producing Compound (15) by reacting Compound (14) with ammonia.

The amount of ammonia used in the present step is usually equimolar to excess mole relative to 1 mole of compound (14).

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples of the reaction solvent include water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,2-dimethoxyethane, Dioxane, N, N-dimethylformamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, or a mixed solvent thereof.

The reaction temperature is usually 0 ° C to 200 ° C, preferably room temperature to 150 ° C. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 72 hours.

Recipe D

The compound (19) wherein Z ¹ in the general formula (1) is a hydroxyl group, Z ² is hydrogen and X is CH ₂ can be produced by the following Production Process D.

(Step 13)

This step is a method of reacting the compound (16) with 2- (4,6-dichloropyrimidin-5-yl) acetaldehyde. This reaction can be carried out in the same manner as in Step 7.

(Step 14)

This step is a step of reacting the reaction product of Step 13 with iodosuccinimide to introduce an iodine atom. This reaction can be carried out by the same method as in Step 10.

(Step 15)

This step is a method for producing the compound (19) by reacting the reaction product of Step 14 with ammonia. This reaction can be carried out by the same method as in Step 12.

The compound (20) in which Z ¹ in the general formula (1) is a hydroxyl group, Z ² is hydrogen and X is O is known.

Recipe E

Also, it is preferable that all of R ₁ and R ₂ in the compound (A)

Compound (27), which is a compound showing = CH-, can be prepared by the following Production Method E.

[Wherein R ₃ , R ₄ and R ₅ are the same as above].

(Step 16)

This step is a method of obtaining the compound (22) by reducing the carboxyl group of the compound (21). This step is carried out in the presence of a reducing agent. In this step, the reducing agent may be used in an amount of 1 to 20 moles, preferably 1 to 5 moles per 1 mole of the compound (21). Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, borane reagent (for example, diborane), and diisobutylaluminum hydride.

As the solvent, methanol, ethanol, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 17)

This step is a step wherein compound (23) is synthesized by Mitsunobu reaction using compound (22) as a starting material and 4-chloro-5-iodo-7H-pyrrolo [ ). ≪ / RTI >

This reaction can be carried out by the same method as in Step 1.

(Step 18)

This step is a method for producing the compound (24) by reacting the compound (23) with ammonia. This reaction can be carried out by the same method as in Step 12.

(Step 19)

This step is a step of preparing Compound (25) by deprotecting the protection of the hydroxyl group of Compound (24). This reaction can be carried out by the same method as in Step 11.

(Step 20)

This step is a method for producing Compound (26) by Mitsunobu reaction using Compound (25) as a raw material and tert-butylsulfamoylcarbamate as a nucleophile.

This reaction can be carried out by the same method as in Step 1.

(Step 21)

This step is a step for producing the compound (27) by using the compound (26) as a raw material and deprotecting the protection of the amino group after the coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.). This reaction can be carried out in the same manner as in Step 3 and Step 4.

Recipe F

Compound (29), which is a compound represented by Formula (A), wherein R ₁ and R ₂ are the same or different and represent hydrogen, fluorine, hydroxyl, amino, cyano or a protected form thereof, can do.

Wherein X, R ₃ , R ₄ , R ₅ , Z ¹ and Z ² are as defined above.

(Step 22)

This step is a method for producing the compound (28) by using the compound (1) as a raw material and performing a coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.). This reaction can be carried out by the same method as in Step 3.

(Step 23)

This step is a method for producing compound (29) by reacting compound (28) with a sulfamoylating reagent.

This reaction can be carried out by the same method as in Step 2. This step may be carried out in multiple stages, if necessary, or the deprotection reaction may be suitably combined.

Recipe G

Further, the compound (32) in the compound (A) can be produced by the following Production Method G.

Wherein P ₁ , Z ¹ , and Z ² are the same as described above. Rb is the same as the R _6. And Rc represents an alkyl group which may be substituted.

(Step 24)

This step is a method of obtaining compound (31) by oxidizing compound (30). This step is carried out in the presence of an oxidizing agent. In the present step, the oxidizing agent may be used in an amount of usually 1 to 20 moles, preferably 1 to 5 moles, per 1 mole of the compound (30). Examples of the oxidizing agent include oxone, m-chloroperbenzoic acid, hydrogen peroxide, potassium permanganate and the like.

As the solvent, water, acetone, 2-butanone, acetonitrile, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, Amide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, etc. may be used singly or in combination. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature is usually from 0 占 폚 to the boiling point of the solvent, preferably from 0 占 폚 to 100 占 폚.

(Step 25)

This step is a step of preparing compound (32) by deprotecting the protection of amino group of compound (31). This reaction can be carried out by the same method as in Step 4.

Each of the compounds obtained in each of the processes A to G described above can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography or the like, , The next step can be carried out.

When a compound represented by the general formula (A) or a compound having another antitumor effect has an isomer such as an optical isomer, a stereoisomer, a position isomer, a rotamer, etc., a mixture of any isomer is included in the compound of the present invention . For example, when an optical isomer is present in a compound of the present invention, optical isomers separated from the racemate are also included in the compound of the present invention. These isomers can be obtained as a single compound by known synthesis methods, separation methods (concentration, solvent extraction, column chromatography, recrystallization, etc.).

The compound represented by the general formula (A) or the compound having another antitumor effect can be easily isolated and purified by a conventional separation means. Examples of such means include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography and the like.

The compound represented by the general formula (A) or the compound having another antitumor effect may be a crystal, and a single or a polymorphic mixture in a crystalline form is included in the compound of the present invention. Crystals can be produced by crystallization by applying a known crystallization method. The compound of the present invention may be a solvate (e.g., hydrate, etc.), or may be a non-solvated cargo, all of which are included in the compound of the present invention. The compounds of the present invention labeled with isotopes (e.g., 3H, 14C, 35S, 125I, etc.) are also included in the compounds of the present invention.

A prodrug of a compound represented by the general formula (A) or a prodrug of a compound having another antitumor effect is a compound that converts into a compound by a reaction with an enzyme, a gastric acid or the like under physiological conditions in vivo, Refers to a compound that changes into a compound by causing oxidation, reduction, hydrolysis, or the like to change into a compound, hydrolysis or the like by stomach acid or the like. Further, the prodrug of the compound may be changed to a compound under the physiological conditions described in Hirokawa Shoten 1990, "Development of Pharmaceuticals" Vol. 7, Molecular Design, pp. 163-198.

The salt of the compound represented by the general formula (A) or the salt of the compound having another antitumor effect means those which are conventional in the field of organic chemistry and include, for example, a base in the carboxyl group in the case of having a carboxyl group An addition salt or a salt of an acid addition salt in the amino group or the basic heterocycloalkyl group in the case of having an amino group or a basic heterocycloalkyl group. The salt of the compound represented by the general formula (A) or the salt of the compound having another antitumor effect includes a pharmaceutically acceptable salt of the compound.

Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; Alkaline earth metal salts such as calcium salts and magnesium salts; For example, ammonium salts; Organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt and N, N'-dibenzylethylenediamine salt And the like.

Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; Organic acid salts such as acetate, formate, maleate, fumarate, tartarate, citrate, ascorbate and trifluoroacetate; Examples thereof include sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate. Preferably, the acid addition salt is a hydrochloride salt.

The compound represented by the general formula (A) or the compound having another antitumor effect is useful as an antitumor effect enhancer. Further, the compound represented by the general formula (A) or the compound having another antitumor effect is useful as an antitumor agent in combination with a compound having another antitumor effect. The type of malignant tumor to be treated is not particularly limited. In addition, the type of tumor organs of the tumor is not particularly limited. Cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, pancreatic cancer, pancreatic cancer, Colon cancer, pancreatic cancer, lung cancer, prostate cancer, breast cancer, osteosarcoma sarcoma, skin cancer, and the like. The term " osteosarcoma "

Examples of hematopoietic tumors include, for example, bone marrow tumors (for example, lymphoid leukemia, myeloid leukemia, acute leukemia, chronic leukemia, and the like), and lymphoid tumors.

(AML) and related progenitor cell tumors, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), and the like, as bone marrow tumors, more specifically, It is preferably acute leukemia, particularly preferably acute myelogenous leukemia.

Examples of lymphocytic tumors include squamous lymphoma tumors, mature B cell tumors, mature T cells and NK cell tumors, Hodgkin's lymphoma, and the like, preferably squamous lymphoma tumors, mature B cell tumors, mature T cells Cells and NK cell tumors. It is also called lymphocytic lymphoma and non-Hodgkin's lymphoma.

Examples of lymphocytic lymphocytic tumors include B lymphocytic leukemia / lymphoma, T lymphocytic leukemia / lymphoma (ALL), and other subtyped lymphomas including AgNK cell lymphoma. Preferably, T lymphocyte / Leukemia / lymphoma.

Mature B cell tumors include chronic lymphocytic leukemia / small cell lymphoma (CLL / SLL), B cell lymphocytic leukemia (B-PLL), splenic marginal lymphoma (SMZL), hairy cell leukemia (HCL) Cell lymphomas (DLBCL, Burkitt lymphoma), and the like, and preferably include, but are not limited to, lymphomas, lymphomas, plasmacytoma, MALT lymphoma, follicular lymphoma, mantle cell lymphoma , Plasma cell tumor, and B cell lymphoma.

Plasma cell tumors are preferably multiple myeloma.

Mature T and NK cell tumors include, but are not limited to, T cell lymphocytic leukemia (T-PLL), aggreational NK cell leukemia / lymphoma, adult T cell leukemia / lymphoma, peripheral T cell lymphoma- And the like.

Hodgkin's lymphoma includes nodular lymphocytic Hodgkin's lymphoma, classical Hodgkin's lymphoma, tuberous sclerosing classical Hodgkin's lymphoma, mixed cell type classical Hodgkin's lymphoma, and the like.

Hematopoietic tumors are known as diagnostic methods and classification methods. FAB classification has been conventionally known, and recently WHO classification has also been used. The compound represented by the general formula (A) or the compound having another antitumor effect is widely useful for each hematopoietic tumor classified by any classification method.

When a compound represented by the general formula (A) or a compound having another antitumor effect is used as a medicament, various forms of administration can be employed depending on the purpose of prevention or treatment, May be, for example, an oral preparation, an injection, a suppository, an ointment, an adhesive, and an eyedrop, and preferably an injection (intravenous injection, etc.) is employed. These dosage forms can be prepared by known formulation methods by those skilled in the art. The compound represented by the general formula (A) or the compound having another antitumor effect may be formulated as a single composition, or may be formulated as two or more compositions.

As the pharmaceutical carrier, various organic or inorganic carrier substances for use as a preparation material are used. It is also possible to use a pharmaceutical agent such as an excipient, a binder, a disintegrant, a lubricant and a coating agent in a solid preparation, a solvent, a solubilizing agent, An isotonic agent, a pH adjuster, a pH buffering agent, an anhydrous agent, and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, mating agents, fodder, and stabilizers may be used.

In the case of preparing an oral liquid preparation, a solution, syrup, elixir, etc. may be prepared by a conventional method by adding a mating agent, a buffer, a stabilizer, a fodder or the like to the compound of the present invention.

For example, polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride and the like may be added to the compound of the present invention, and if necessary, Tween 80 (registered trademark) And then adding the same surfactant or the like, followed by a conventional method.

In the case of producing an ointment agent, a base, a stabilizer, a wetting agent, a preservative, and the like which are generally used in the compound of the present invention are compounded as needed and mixed and formulated by a conventional method.

As the base, liquid paraffin, white petrolatum, bleached wax, octyldodecyl alcohol, paraffin and the like can be mentioned.

Examples of the excipient include lactose, white sugar, D-mannitol, starch, crystalline cellulose, calcium silicate and the like.

Examples of the binder include hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, sugar powder, and hypromellose.

Examples of disintegrators include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially-alpha-starch, and the like.

Examples of the lubricant include talc, magnesium stearate, sucrose fatty acid ester, stearic acid, stearyl sodium fumarate, and the like.

Examples of the coating agent include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, white sugar, and the like.

Examples of the solvent include water, propylene glycol, and physiological saline.

Examples of the dissolution aid include polyethylene glycol, ethanol, alpha -cyclodextrin, Macrogol 400, polysorbate 80 and the like.

Examples of the suspending agent include carrageenan, crystalline cellulose, carmellose sodium, and polyoxyethylene hardened castor oil.

Examples of isotonic agents include sodium chloride, glycerin, and potassium chloride.

Examples of the pH adjuster and pH buffer include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate and the like.

Examples of the wettable agent include proccine hydrochloride and lidocaine.

Examples of the preservative include ethyl paraoxybenzoate, cresol, benzalkonium chloride and the like.

Examples of the antioxidant include sodium sulfite, ascorbic acid, natural vitamin E and the like.

Examples of the colorant include titanium oxide, ferric trioxide, edible blue No. 1, and copper chlorophyll.

Examples of the mating agent and the replicating agent include aspartame, saccharin, sucralose, l-menthol, mint flavor and the like.

Examples of the stabilizer include sodium pyrophosphate, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

In the case of producing an adhesive agent, the above ointment, cream, gel, paste and the like may be applied to an ordinary support by a common method.

As the support, woven fabric including cotton, staple fiber, chemical fiber, nonwoven fabric; Or a film or foam sheet of soft vinyl chloride, polyethylene, polyurethane or the like is suitable.

The amount of the compound represented by the general formula (A) or the compound having another antitumor effect to be compounded in each of the above-mentioned dosage unit forms differs depending on the symptom of the patient to which it is applied, or on the formulations thereof. The amount of the compounds of the present invention, but are not constant, in general, per dosage unit form, it is preferable that an amount corresponding to 10mg / m ² to about 1000mg / m ² in the oral, injections, suppositories.

The dose per day of the medicament having the above-mentioned dosage form varies depending on the patient's symptoms, body weight, age, sex, etc. and can not be uniformly determined. However, the compound is usually administered in an amount of 13.9 to 1500 mg, Preferably 50 to 1000 mg, and it is preferable to administer it once or twice or three times a day.

The amount of the compound having other antitumor effect to be compounded in each of the above-mentioned dosage unit forms is appropriately set depending on the kind of the antitumor agent to be used, the symptom of the patient, the formulation and the like. Also, the dose per day for the medicament having the above-mentioned dosage form is likewise appropriately set.

When two or more different compositions are used as the compound having an antitumor effect different from the compound represented by the general formula (A), the administration method of the composition is not particularly limited as far as it can exert the enhancing action of the present invention May be administered simultaneously, sequentially, or at intervals. The order of administration of the composition is not particularly limited, and the antineoplastic agent containing the compound represented by the general formula (A) may be administered before, simultaneously with, or after the antineoplastic agent containing the compound having another antitumor effect.

In another embodiment, there is provided an antitumor agent comprising a combination of a compound represented by formula (A) and a compound having another antitumor effect.

As used herein, the terms "combination" and "combination" refer to a combination of a compound represented by formula (A) and a compound having another antitumor effect in a single composition Or as two separate compositions, or two separate compositions may be administered sequentially or as a separate composition. The compound represented by the general formula (A) may be used or administered before, concurrently with, or after the compound having another antitumor effect.

In another embodiment, there is provided the use of a compound represented by the general formula (A) or a salt thereof for enhancing the antitumor effect of an antitumor agent containing a compound having another antitumor effect.

In another embodiment, use of a compound represented by the general formula (A) or a salt thereof for the preparation of an antitumor effect enhancer of an antitumor agent containing a compound having another antitumor effect is provided.

In another embodiment, there is provided the use of a compound represented by the general formula (A) or a salt thereof for the preparation of an antitumor agent in combination with a compound having another antitumor effect.

In another embodiment, there is provided a pharmaceutical composition for the prevention and / or treatment of a tumor comprising a compound represented by the general formula (A) or a salt thereof and a compound having another antitumor effect.

In another embodiment, a method for enhancing antitumor effect of another antitumor agent comprising administering to a patient an amount of a compound represented by the general formula (A) or a salt thereof in an amount effective for prevention and / or treatment of tumor is provided do.

In another embodiment, there is provided a pharmaceutical composition comprising a compound represented by the general formula (A) or a salt thereof and a compound having another antitumor effect in combination with a tumor / RTI > and / or < / RTI >

In another embodiment, the compound represented by the general formula (A) or its salt and the compound having another antitumor effect as a combination preparation for simultaneous, sequential, or spaced use in the prevention and / Is provided.

Example

Hereinafter, the present invention will be described in more detail with reference to the following Reference Examples, Test Examples and Examples, but the present invention is not limited thereto at all.

The various reagents used in the examples were commercially available unless otherwise specified.

Silica gel column chromatography was carried out using a prepack (registered trademark) SI manufactured by Moritech, a KP-Sil (registered trademark) Silica prepacked column made by BioTaj Inc., or a HP-Sil (registered trademark) Silica prepacked column made by Biotage .

For the basic silica gel column chromatography, Preppac (registered trademark) NH manufactured by MORITEX Co., Ltd. or KP-NH (registered trademark) prepacked column manufactured by BioTech Co., Ltd. was used.

For preparative thin layer chromatography, Kieselgel 占 60F254 manufactured by Merck, Art. 5744 or Wako Corp. NH2 silica gel 60F254 plate was used.

NMR spectra were measured using an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with an AL400 (400 MHz; JEOL), a Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an OMNMR probe Tetramethylsilane was used as an internal standard in the case where tetramethylsilane was contained in the middle solvent, and the NMR solvent was used as an internal standard in the other cases, and the total delta value was expressed in ppm.

The microwave reaction was performed using a DiscoverS class manufactured by CEM or an initiator manufactured by Biotage.

Further, the LCMS spectrum was measured using ACQUITY SQD (quadrupole type) manufactured by Waters under the following conditions.

Column: YMC-Triart C18 manufactured by YMC, 2.0 X 50 mm, 1.9 탆

MS detection: ESI positive

UV detection: 254 and 210 nm

Column flow rate: 0.5 mL / min

Mobile phase: water / acetonitrile (0.1% formic acid)

Injection volume: 1 μL

The gradient (table 1)

Time (minutes) water(%) Acetonitrile (%)

0 95 5

0.1 95 5

2.1 5 95

3.0 STOP

In addition, reverse phase preparative HPLC purification was carried out using a Waters product dispensing system under the following conditions.

Column: YMC-Actus Triart C18, 20X50 mm, 5 μm, YMC-Actus Triart C18, 20 × 10 mm, 5 μm, manufactured by YMC,

UV detection: 254 nm

MS detection: ESI positive

Column flow rate: 25 mL / min

Mobile phase: water / acetonitrile (0.1% formic acid)

Injection amount: 0.1-0.5 mL

<< Abbreviation >>

s: singlet

d: doublet

t: triplet

q: quartet

m: Multiplet

brs: Broad singlet

brm: Broad Multiplet

dd: double doublet

dt: double triplet

dq: double quartet

ddd: double double doublet

DMSO-D ₆ : To a solution of intermediate dimethylsulfoxide

CDCl _3: heavy chloroform

CD ₃ OD: MeOH

PdCl ₂ (dppf) CH ₂ Cl ₂ : 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex

n-Butyl lithium: N-butyl lithium

Reference Example 1

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-isoquinoline- 3a, 4,6,6a-tetrahydropro [3,4-d] [1,3] dioxol-6-yl] methanol

Pyrrolo [2,3-d] pyrimidin-7-yl) -5- (hydroxymethyl) tetrahydrofuran-2-carboxylic acid Diol (15 g, 34.8 mmol) was suspended in acetone (120 mL) and 2,2-dimethoxypropane (24.4 mL) at room temperature, and then boron trifluoride diethyletherate (27.8 mL , 6.3 eq) was added dropwise so that the internal temperature was maintained at 10 캜 or lower. The obtained mixture was stirred for 75 minutes in an ice bath, and then a 5M aqueous sodium hydroxide solution (60 mL) was slowly added dropwise to maintain the internal temperature at 15 캜 or lower. The acetone was distilled off under reduced pressure, chloroform and water were added, and the mixture was stirred for about 5 minutes. The reaction solution was filtered through celite to remove insolubles, and the aqueous layer was separated and extracted twice with chloroform. The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The brown oil of the residue was suspended in hexane (50 mL) and stirred for 2 hours. The resulting solid was collected by filtration and dried to give the title compound (10.7 g, 71%) as a light brown solid.

_{^{1 H-NMR (CDCl 3)}} δ: 8.23 (1H, s), 7.12 (1H, s), 6.40 (1H, d, J = 11.5㎐), 5.76-5.74 (2H, brs), 5.69 (1H, d J = 5.1 Hz), 5.24-5.22 (1H, m), 5.10-5.08 (1H, m), 4.49 (1H, s), 3.97-3.94 ㎐), 1.63 (3H, s), 1.36 (3H, s). LCMS (ESI) m / z 433 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 7 - ((3aR, 4R, 6R, 6aR) -6- (Aminomethyl) -2,2-dimethyltetrahydrofuro [3,4- d] [1,3] dioxol- ) -5-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-amine

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-3a, 4a, 4a, 3,4-d] [1,3] dioxol-6-yl] methanol (3.2 g, 7.4 mmol) and phthalimide (2.18 g, 14.8 mmol) were dissolved in tetrahydrofuran 30 mL), and then triphenylphosphine (2.9 g, 11.1 mmol) was added under ice-cooling stirring. After dissolving triphenylphosphine, diisopropyl azodicarboxylate (2.2 mL, 11.1 mmol) was added dropwise under ice-cooling with stirring. After the reaction solution was stirred for 1.5 hours under ice-cooling, the reaction solution was distilled off under reduced pressure, and ethanol (30 mL), water (9 mL) and hydrazine monohydrate (1.2 mL, 24.7 mmol) were added to the residue at room temperature. The reaction solution was stirred overnight under reflux, and then the reaction solution was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the aqueous layer was separated and extracted with ethyl acetate. After the combined organic layers were dried over sodium sulfate and the solvent was distilled off, the residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (3.23 g, quant.) As a yellow solid .

_{^{1 H-NMR (CDCl 3)}} δ: 8.28 (1H, s), 7.19 (1H, s), 6.13 (1H, d, J = 3.2㎐), 5.65-5.63 (2H, brs), 5.23 (1H, dd J = 6.7, 3.2 Hz), 4.93 (1H, dd, J = 6.7, 4.0 Hz), 4.18-4.14 (1H, m), 3.04 dd, J = 13.4, 5.9 Hz), 1.61 (3H, s), 1.37 (3H, s). LCMS (ESI) m / z 432 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of tert-butyl-N - ((3aR, 4R, 6R, 6aR) -6- (4-Amino-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- 3,4-d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate The title compound

3,4-d] [1,3] dioxol-4-yl) -5- (4-fluoropyridin- (3.23 g) was dissolved in chloroform (40 mL), and then a solution of 1-aza-4-azoniabicyclo [2.2.2 Diazabicyclo [2.2.2] octane monohydrochloride (Organic Letters, 2012, 10, 2626-2629) (6.2 g, , 14.1 mmol). After the reaction solution was stirred at room temperature for 2 hours, the precipitate was separated by filtration and washed with chloroform. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol) to give the title compound (4.0 g, 88%) as a milky white solid.

_{^{1 H-NMR (CDCl 3)}} δ: 9.27-9.25 (1H, brs), 8.50 (1H, s), 7.08 (1H, s), 6.04-6.02 (2H, brs), 5.65 (1H, d, J = Dd, J = 6.3, 4.7 Hz), 5.07 (1H, dd, J = 6.3, 2.2 Hz), 4.50 (1H, d, J = 2.2 Hz), 3.63-3.49 m), 1.61 (3H, s), 1.44 (9H, s), 1.35 (3H, s). LCMS (ESI) m / z 611 [M + H] &lt; ^{+ &}

(Step 4) Reference Example Synthesis of Compound 1

7H-pyrrolo [2,3-d] pyrimidin-7-yl) - 2 - ((3aR, 4R, 6R, 6aR) (20 mg, 0.033 mmol), 2-ethynyl-1,3-dioxolan-4-ylmethyl) sulfamoylcarbamate (3 mg, 0.0043 mmol), copper iodide (1 mg, 0.0053 mmol) and diisopropylethylamine (0.011 mmol) were added to a solution of 4- mL, 0.066 mmol) was suspended in tetrahydrofuran (0.20 mL). After the reaction solution was stirred at 70 ° C for 2 hours, a mixed solution (0.60 mL) of trifluoroacetic acid / water = 4/1 was added at room temperature, and the mixture was stirred overnight at room temperature. After the solvent was distilled off, the residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (14 mg, 91%) as a yellow powder.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 7.68 (1H, s), 7.45-7.37 (1H, m), 7.10-7.04 (2H, m), 5.86 (1H, d, J = 7.3 Hz), 4.86-4.81 (1H, m), 4.31-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 481 [M + H] &lt; ^{+ &}

(Step 5)

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine hydrochloride

6R, 6aR) -6- (4-Amino-5 - ((2,6-difluorophenyl) ethynyl) -7H-pyrrolo [2,3 yl) methyl) sulfamoylcarbamate (8.05 g, 12.9 &lt; RTI ID = 0.0 & mmol) were dissolved in acetonitrile (120 mL) and concentrated hydrochloric acid (10.8 mL, 129 mmol) was added at room temperature. After stirring at room temperature for 6 hours, acetonitrile (80 mL) was added, and the mixture was stirred overnight at room temperature. The precipitate was filtered out, washed with acetonitrile (80 mL) and dried to give the title compound hydrochloride (5.93 g, 88%) as a white solid.

^{1 H-NMR (DMSO-D} 6) δ: 8.42 (1H, s), 8.25 (1H, s), 7.55 (1H, tt, J = 8.1, 7.7㎐), 7.28 (2H, dd, J = 8.4, J = 6.6 Hz), 4.48 (1H, dd, J = 6.6, 5.1 Hz), 4.12-4.10 (lH, brs) m), 4.06-4.03 (1H, m), 3.22 (1H, dd, J = 13.9,5.5 Hz), 3.12 (1H, dd, J = 13.2, 5.5 Hz). LCMS (ESI) m / z 481 [M + H] &lt; ⁺ &gt;.

Reference Example 2

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2 , 3-d] pyrimidin-5-yl] -2- (o-tolyl) thiazole

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- Yl) methyl) sulfamoylcarbamate (300 mg, 0.491 mmol), 1,1'-bis (diphenylphosphoryl) (40.1 mg, 0.049 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -pyrrolidine- ) -2- (o-tolyl) thiazole (295 mg, 0.982 mmol) was suspended in 2 M aqueous sodium carbonate solution (1.23 mL) and dimethoxyethane (5 mL) and stirred at 70 ° C for 17 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then concentrated. The residue was dissolved in acetonitrile (1 mL), trifluoroacetic acid (0.5 mL) and water (0.1 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to obtain the desired product (110 mg, 43%) as a yellowish white solid.

^{1 H-NMR (DMSO-D} 6) δ: 8.10 (1H, s), 8.08 (1H, s), 8.06 (1H, s), 7.70 (1H, d, J = 7.3㎐), 7.46-7.35 (3H d, J = 6.6 Hz), 5.60 (1H, d, J = 4.8 Hz), 4.60 (1H, , dt, J = 6.6,5.5 Hz), 4.14-4.11 (1H, m), 4.08-4.04 (1H, m), 2.53 (3H, s). LCMS (ESI) m / z 518 [M + H] &lt; ⁺ &gt;.

Reference Example 3

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] methyl] ] Tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, using 1- (benzyloxy) -4-ethynylbenzene instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 8.29 (1H, s), 7.44-7.27 (8H, m), 6.96 (2H, d, J = 8.8㎐), 5.69 (1H, d, J = 6.8㎐), 5.10 (2H, s), 4.87-4.84 (1H, m), 4.36-4.33 (2H, m), 3.46-3.40 (4H, m). LCMS (ESI) m / z 551 [M + H] &lt; ⁺ &gt;.

Reference Example 4

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 5- (2-pyridyl) -2-thienyl] ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 2- (5-ethynylthiophen-2-yl) pyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.49 (1H, d, J = 5.1㎐), 8.25 (1H, s), 7.84-7.82 (2H, m), 7.64 (1H, s), 7.64 (1H, d, J = 4.1 Hz), 7.35 (1H, d, J = 4.1 Hz), 7.30-7.27 (1H, m), 5.87 4.32-4.30 (1H, m), 4.28-4.25 (1H, m), 3.39-3.30 (2H, m). LCMS (ESI) m / z 528 [M + H] &lt; ⁺ &gt;.

Reference Example 5

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2 , 3-d] pyrimidin-5-yl] -2- (2-methoxyphenyl) thiazole

According to the same manner as in Reference Example 2, except for using 2- ((4-fluorophenyl) -1,3-dioxaborolan-2-yl) 2-methoxyphenyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.20 (1H, s), 8.17 (1H, dd, J = 7.7, 1.8㎐), 7.88 (1H, s), 7.84 (1H, s), 7.49 (1H, d, J = 1.1,8.8 Hz), 7.24 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 7.7 Hz), 5.98 (1H, m), 4.36 (1H, dd, J = 5.5, 2.9 Hz), 4.29-4.26 (1H, m), 4.08 (3H, s), 3.47-3.37 (2H, m). LCMS (ESI) m / z 534 [M + H] &lt; ⁺ &gt;.

Reference Example 6

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 1-naphthyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 1-ethynylnaphthalene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.36 (1H, d, J = 8.0㎐), 8.26 (1H, s), 7.93-7.90 (2H, m), 7.77 (1H, d, J = 7.6㎐) , 7.73 (1H, s), 7.64-7.47 (3H, m), 5.90 (1H, d, J = 6.8 Hz), 4.87-4.84 (1H, m), 4.34-4.32 (1 H, m), 3.39-3.30 (2 H, m). LCMS (ESI) m / z 495 [M + H] &lt; ⁺ &gt;.

Reference Example 7

2-yl] -5- (3-phenylpyridin-2-yl) -5- [(2R, 3R, 4S, 5R) -3,4-dihydroxy- Propyl-l-vinyl) pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using prop-2-yn-1-ylbenzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.18 (1H, s), 7.43 (1H, s), 7.40 (2H, d, J = 7.6㎐), 7.33 (2H, dd, J = 7.6, 7.3㎐) , 7.24 (1H, t, J = 7.3 Hz), 5.80 (1H, d, J = 6.8 Hz), 4.87-4.80 (1H, m), 4.30-4.25 ), 3.88 (2H, s), 3.39-3.30 (2H, m). LCMS (ESI) m / z 459 [M + H] &lt; ⁺ &gt;.

Reference Example 8

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] quinoline

According to Reference Example 1, Step 4, 4-ethynylquinoline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.83 (1H, d, J = 4.4㎐), 8.40 (1H, d, J = 9.5㎐), 8.28 (1H, s), 8.06 (1H, d, J = D, J = 8.8, 8.0 Hz), 7.76-7.73 (2H, m), 5.93 (1H, d, J = 6.6 Hz), 4.87-4.80 1H, m), 4.35-4.30 (1H, m), 4.29-4.26 (1H, m), 3.40-3.30 (2H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 9

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 4- (phenoxymethyl) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 1-ethynyl-4- (phenoxymethyl) benzene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 7.61 (1H, s), 7.57 (2H, d, J = 8.3㎐), 7.49 (2H, d, J = 8.3㎐), 7.28 (2H, dd, J = 8.0,7.8 Hz), 7.00 (2H, d, J = 7.8 Hz), 6.94 (1H, t, J = 8.0 Hz), 5.86 (2H, s), 4.85-4.75 (1H, m), 4.35-4.30 (1H, m), 4.28-4.25 (1H, m), 3.40-3.30 (2H, m). LCMS (ESI) m / z 551 [M + H] &lt; ⁺ &gt;.

Reference Example 10

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Phenylcyclopropyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using (1-ethynylcyclopropyl) benzene instead of 2-ethynyl-1,3-difluorobenzene.

¹ H-NMR (CD ₃ OD)?: 8.21 (1H, s), 7.46 (1H, s), 7.43-7.40 (2H, m), 7.32 (1H, m), 5.82 (1H, d, J = 6.8 Hz), 4.82-4.79 (1H, m), 4.30-4.28 m), 1.54-1.50 (2H, m), 1.40-1.37 (2H, m). LCMS (ESI) m / z 485 [M + H] &lt; ⁺ &gt;.

Reference Example 11

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] isoquinoline

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynylisoquinoline instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.56 (1H, d, J = 8.0㎐), 8.45 (1H, d, J = 8.0㎐), 8.23 (1H, s), 8.19 (1H, s), (2H, s), 7.99 (1H, d, J = 8.0 Hz) (1H, d, J = 6.8 Hz), 5.48-5.46 (1H, brs), 5.29-5.25 (1H, brs), 4.63-4.59 (1 H, m), 3.25-3.21 (1 H, m), 3.18-3.12 (1 H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 12

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2 , 3-d] pyrimidin-5-yl] -2-phenyl-oxazole

According to the same manner as in Reference Example 2, except that 2-phenyl (4-methylphenyl) -1,3,5-tetramethyl-1,3,2-dioxaborolan- -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.28 (1H, s), 8.07-8.00 (2H, m), 7.93 (1H, s), 7.51-7.49 (3H, m), 7.48 (1H, s), (2H, m), 4.33 (1H, dd, J = 5.4, 3.2 Hz), 4.26-4.22 (1H, m), 3.45-3.35 m). LCMS (ESI) m / z 488 [M + H] &lt; ⁺ &gt;.

Reference Example 13

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] quinoline

According to Reference Example 1, Step 4, 5-ethynylquinoline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.91 (1H, dd, J = 4.4, 1.7㎐), 8.84-8.78 (1H, m), 8.26 (1H, s), 8.04 (1H, d, J = 8.5 (1H, d), 7.89 (1H, dd, J = 7.9,1.1 Hz), 7.81 (1H, s), 7.80-7.76 (d, J = 6.8 Hz), 4.87-4.82 (1H, m), 4.35-4.33 (1H, m), 4.29-4.26 (1H, m), 3.45-3.36 (2H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 14

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2- (trifluoromethoxy) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynyl-2- (trifluoromethoxy) benzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.26 (1H, s), 7.68-7.62 (1H, m), 7.65 (1H, s), 7.50-7.46 (1H, m), 7.42-7.38 (2H, m ), 5.86 (1H, d, J = 7.1 Hz), 4.86-4.81 (1H, m), 4.31-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 529 [M + H] &lt; ⁺ &gt;.

Reference Example 15

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-methoxy-1-naphthyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 1-ethynyl-2-methoxynaphthalene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.89-7.80 (2H, m), 7.66-7.57 (1H, m), 7.64 (1H, s), 7.58-7.54 (1H, m ), 7.42-7.36 (2H, m), 5.90 (1H, d, J = 8.0 Hz), 4.83-4.81 (1H, m), 4.37-4.33 4.06 (3 H, s), 3.40-3.35 (2 H, m). LCMS (ESI) m / z 525 [M + H] &lt; ⁺ &gt;.

Reference Example 16

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,6-dimethoxyphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 2-ethynyl-1,3-dimethoxybenzene was used instead of 2-ethynyl-1,3-difluorobenzene to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.22 (1H, s), 7.50 (1H, s), 7.28 (1H, t, J = 8.5㎐), 6.69 (2H, d, J = 8.5㎐), 5.86 (1H, d, J = 6.8 Hz), 4.83-4.81 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 , m). LCMS (ESI) m / z 505 [M + H] &lt; ⁺ &gt;.

Reference Example 17

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] quinoline

According to Reference Example 1, Step 4, 8-ethynylquinoline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.99 (1H, dd, 4.1,1.7㎐), 8.33 (1H, dd, 8.5, 1.7㎐), 8.22 (1H, s), 7.91 (1H, s), 7.90 (2H, m), 7.58-7.52 (2H, m), 5.86 (1H, d, J = 6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 (1 H, m), 3.40-3.35 (2 H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 18

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfam Methylamino] methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1- (difluoromethoxy) -2-ethynylbenzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.62 (1H, s), 7.58 (1H, d, J = 7.8, 1.7㎐), 7.43-7.39 (1H, m), 7.28- (2H, m), 7.01 (1H, t, J = 7.2 Hz), 5.86 (1H, d, J = 6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 -4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 511 [M + H] &lt; ⁺ &gt;.

Reference Example 19

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrazolo [4,3-b] pyridin-5-yl) ethynyl] pyrrolo [2,3- d] pyrimidine

According to Reference Example 1, Step 4, 5-ethynyl-1H-pyrazolo [4,3-b] pyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 8.23 (1H, s), 8.06 (1H, d, J = 8.8㎐), 7.75 (1H, s), 7.64 (1H, d, J = 8.8 Hz), 5.89 (1H, d, J = 6.8 Hz), 4.87-4.85 (1H, m), 4.34-4.30 (1H, m), 4.27-4.25 , m). LCMS (ESI) m / z 486 [M + H] &lt; ⁺ &gt;.

Reference Example 20

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [ Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 4-ethynyl-3-fluoroaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

¹ H-NMR (CD ₃ OD)?: 8.22 (1H, s), 7.48 (1H, s), 7.21-7.17 (1H, m), 6.46-6.41 = 6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.28 (1H, m), 4.27-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 478 [M + H] &lt; ⁺ &gt;.

Reference Example 21

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- -1-ylethynyl) pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynyl-2,3-dihydro-1H-indene instead of 2-ethynyl-1,3-difluorobenzene.

¹ H-NMR (CD ₃ OD)?: 8.19 (1H, s), 7.42 (1H, s), 7.42-7.38 (1H, m), 7.26-7.18 (2H, m), 2.42-2.54 (1H, m), 3.40-3.35 (2H, m) 2.19-2.11 (1 H, m). LCMS (ESI) m / z 485 [M + H] &lt; ⁺ &gt;.

Reference Example 22

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-methylsulfonylphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynyl-2- (methylsulfonyl) benzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 8.07 (1H, dd, J = 7.7, 1.3㎐), 7.79 (1H, dd, J = 7.7, 1.3㎐), 7.77 (1H, (1H, s), 7.75-7.70 (1H, m), 7.62-7.57 (1H, m), 5.89 (1H, d, J = 6.8 Hz), 4.85-4.81 , 4.28-4.24 (1H, m), 3.40-3.35 (2H, m), 3.30 (3H, s). LCMS (ESI) m / z 523 [M + H] &lt; ⁺ &gt;.

Reference Example 23

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-phenyl] morpholine

(Step 1) Synthesis of 4- (4-ethynyl-3,5-difluorophenyl) morpholine

2-ethynyl-1,3,5-trifluorobenzene (52 mg, 0.33 mmol) and cesium carbonate (163 mg, 0.50 mmol) were dissolved in N, N-dimethylformamide (0.50 mL). Morpholine (0.044 mL, 0.50 mmol) was added at room temperature and stirred overnight at 80 &lt; 0 &gt; C. After air-cooling to room temperature, ethyl acetate (2.0 mL) and saturated aqueous ammonium chloride solution (1.0 mL) were added in order to obtain an aqueous layer and an organic layer. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, And distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 4- (4-ethynyl-3,5-difluorophenyl) morpholine (40 mg, 54% .

_{^{1 H-NMR (CDCl 3)}} δ: 6.37 (2H, d, J = 10.7㎐), 3.83 (4H, dd, J = 5.7, 4.2㎐), 3.40 (1H, s), 3.19 (4H, dd, J = 5.7, 4.2 Hz). LCMS (ESI) m / z 224 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 23

By using 4- (4-ethynyl-3,5-difluorophenyl) morpholine instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4, the title compound was obtained .

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.56 (1H, s), 6.63 (2H, d, J = 11.5㎐), 5.85 (1H, d, J = 7.1㎐), 4.85 4.79 (1H, m), 4.30 (1H, dd, J = 5.6,2.4 Hz) ), 3.27-3.22 (4 H, m). LCMS (ESI) m / z 566 [M + H] &lt; ⁺ &gt;.

Reference Example 24

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 4-ethynyl-3,5-difluoroaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.52 (1H, s), 6.26 (2H, d, J = 10.2㎐), 5.85 (1H, d, J = 6.8㎐), 4.85 -4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23 (1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 25

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 4-dihydroxy-4H-pyrrolo [ -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3,5-difluoro-N-methylaniline

According to the procedure of Reference Example 23, Step 1, methylamine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 6.11 (2H, d, J = 10.6 Hz), 4.22-4.14 (1H, brm), 3.39 (1H, s), 2.84 (3H, s). LRMS (ESI) m / z 168 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 25

According to Reference Example 1, Step 4, 4-ethynyl-3,5-difluoro-N-methylaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 8.18 (1H, brs), 8.03 (1H, dd, J = 7.7, 1.1㎐), 7.53 (1H, s), 7.48 (1H, d, J = 7.0 Hz), 4.86-4.81 (1H, m), 4.32 (1H, dd, J = , 2.2 Hz), 4.27-4.25 (1H, m), 3.43-3.34 (2H, m), 2.79 (3H, s). LCMS (ESI) m / z 510 [M + H] &lt; ⁺ &gt;.

Reference Example 26

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of N-ethyl-4-ethynyl-3,5-difluoroaniline

According to Reference Example 23, Step 1, ethylamine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 6.10 (2H, d, J = 10.3 Hz), 4.07-4.00 (1H, brm), 3.38 (1H, s), 3.18-3.11 , t, J = 7.3 Hz). LRMS (ESI) m / z 182 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 26

Ethyl-4-ethynyl-3,5-difluoroaniline was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4, the title compound was obtained.

¹ H-NMR (CD ₃ OD)?: 8.24 (1H, s), 8.07-8.00 (1H, m), 7.59-7.45 Dd, J = 5.5, 2.6 Hz), 4.26 (1H, ddd, J = 7.0 Hz), 5.89 , 3.41 (1H, d, J = 13.2, 3.7 Hz), 3.36 (1H, dd, J = 13.2, 4.0 Hz) , 1.25 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 524 [M + H] &lt; ^{+ &}

Reference Example 27

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 3- (isopropylamino) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 3-ethynyl-N-isopropylaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.55 (1H, s), 7.11 (1H, t, J = 8.3㎐), 6.79-6.76 (2H, m), 6.67-6.65 ( D, J = 5.6, 2.4 Hz), 4.25 (1H, q, J = 3.2 Hz, 1H), 5.86 (1H, d, J = 6.8 Hz), 4.84-4.79 ), 3.67-3.54 (1H, m), 3.39-3.35 (2H, m), 1.20 (6H, d, J = 6.3Hz). LCMS (ESI) m / z 502 [M + H] &lt; ⁺ &gt;.

Reference Example 28

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [ Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 3-ethynyl-4-fluoroaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.90 (1H, s), 7.38-7.33 (1H, m), 6.99 (1H, t, J = 9.3㎐), 6.70 (1H d, J = 6.1, 2.9 Hz), 6.62-6.56 (3H, m), 5.92 (1H, d, J = 7.1 Hz), 5.40 J = 4.4 Hz), 5.16 (2H, s), 4.57 (1H, dd, J = 12.1, 6.7 Hz), 4.12-4.08 (1H, m), 4.07-4.03 (1H, m), 3.24-3.08 , m). LCMS (ESI) m / z 478 [M + H] &lt; ⁺ &gt;.

Reference Example 29

Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-fluoropyrrolidin- , 4S, 5R) -3,4-dihydroxy-5- [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of (3R) -1- (4-ethynyl-3,5-difluorophenyl) -3-fluoropyrrolidine

According to Reference Example 23, Step 1, (R) -3-fluoropyrrolidine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 6.07 (2H, d, J = 10.3 Hz), 5.38 (1H, d, J = 52.8 Hz), 3.59-3.38 ), 2.27-2.06 (1 H, m). LCMS (ESI) m / z 226 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 29

(3R) -1- (4-ethynyl-3,5-difluorophenyl) -3-fluoro-3-fluorobenzene was obtained in the same manner as in Reference Example 1, Pyrrolidine, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.16 (1H, s), 7.84 (1H, s), 7.35-7.30 (1H, m), 6.58 (2H, s), 6.42 (2H, d, J = D, J = 8.4 Hz), 5.91 (1H, d, J = 7.1 Hz), 5.91 M), 3.61-3.45 (3H, m), 3.41-3.33 (IH, m), 4.56 (1H, dd, J = 12.1, 6.7 Hz), 4.11-4.07 ), 3.24-3.16 (1H, m), 3.14-3.06 (1H, m), 2.30-2.10 (2H, m). LCMS (ESI) m / z 568 [M + H] &lt; ⁺ &gt;.

Reference Example 30

Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-hydroxypyrrolidin- , 4S, 5R) -3,4-dihydroxy-5- [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of (3R) -1- (4-ethynyl-3,5-difluorophenyl) -pyrrolidin-

According to Reference Example 23, Step 1, (R) -pyrrolidin-3-ol was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.02 (2H, d, J = 10.5㎐), 4.63-4.60 (1H, m), 3.50-3.43 (2H, m), 3.40-3.38 (1H, m), 3.33 (1H, dt, J = 3.3, 9.0 Hz), 3.22 (1H, d, J = 10.7 Hz), 2.22-2.11 (1H, m), 2.11-2.06 (1H, m). LCMS (ESI) m / z 224 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 30

(3R) -1- (4-ethynyl-3,5-difluorophenyl) -pyrrolidine-1-carboxylic acid was prepared in accordance with Referential Example 1, Step 4 instead of 2-ethynyl- 3-ol, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.85 (1H, s), 7.36 (1H, dd, J = 7.7, 4.8㎐), 6.60 (2H, s), 6.35 (2H d, J = 11.0 Hz), 5.91 (1H, d, J = 7.0 Hz), 5.39 (1H, m, J = 3.7 Hz), 4.60-4.55 (1H, m), 4.42-4.37 (1H, m), 4.11-4.07 ), 3.24-3.18 (1H, m), 3.16-3.09 (2H, m), 2.07-1.99 (1H, m), 1.94-1.86 (1H, m). LCMS (ESI) m / z 566.3 [M + H] &lt; ⁺ &gt;.

Reference Example 31

4-amino-5- [3- (2,6-difluorophenyl) prop-1-ynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy- [(Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

By using 1,3-difluoro-2- (prop-2-yn-1-yl) benzene instead of 2-ethynyl-1,3-difluorobenzene according to Reference Example 1, , The title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.20 (1H, s), 7.40 (1H, s), 7.36-7.30 (1H, m), 7.04-6.99 (2H, m), 5.79 (1H, d, J = 6.8 Hz), 4.80-4.69 (1H, m), 4.28-4.25 (1H, m), 4.22-4.20 (1H, m), 3.88 (2H, s), 3.39-3.32 (2H, m). LCMS (ESI) m / z 495 [M + H].

Reference Example 32

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-difluoro-4- (2- -Dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

According to Reference Example 23, Step 1, 2 - ((4-ethynyl-3,5-difluorophenyl) amino) ethanol obtained by using 2-aminoethanol instead of morpholine was obtained in Reference Example 1, Step 4 , Instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.20 (1H, s), 7.91 (1H, s), 7.38 (1H, s), 7.03 (2H, t, J = 9.5㎐), 6.61 (2H, brs ), 5.93 (1H, d, J = 6.6 Hz), 5.47-5.36 (1H, m), 5.34-5.18 m), 4.08-4.04 (1H, m), 3.26-3.19 (1H, m), 3.16-3.08 (1H, m), 2.55 (2H, s). LCMS (ESI) m / z 540.3 [M + H] &lt; ⁺ &gt;.

Reference Example 33

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro- Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) pyrrolidin-2-one

The title compound was obtained by using pyrrolidin-2-one instead of morpholine in accordance with Referential Example 23, Step 1.

_{^{1 H-NMR (CDCl 3)}} δ: 7.35 (2H, d, J = 10.0㎐), 3.82 (2H, t, J = 7.2㎐), 3.47 (1H, s), 2.65 (2H, t, J = 8.2 ㎐), 2.23-2.15 (2H, m). LCMS (ESI) m / z 222 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 33

(1- (4-ethynyl-3,5-difluorophenyl) pyrrolidin-2-one was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, , The title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.97 (1H, s), 7.64 (2H, d, J = 10.5㎐), 7.33-7.30 (1H, brs), 6.58 (2H (1H, d, J = 6.8 Hz), 5.92 (1H, d, J = 7.3 Hz), 5.38 M), 3.15-4.02 (1H, m), 3.84 (2H, t, J = 7.2 Hz), 3.27-3.18 (1H, m), 3.15-3.08 , t, J = 8.2 Hz), 2.10-2.02 (2H, m). LCMS (ESI) m / z 564 [M + H].

Reference Example 34

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3-ethoxy-5-fluoro-phenyl]

(Step 1) Synthesis of 4- (3-ethoxy-4-ethynyl-5-fluorophenyl) morpholine

4- (4-ethynyl-3,5-difluorophenyl) morpholine (100 mg, 0.448 mmol) was dissolved in ethanol (3 mL). Sodium ethoxide (21 wt% ethanol solution, 0.168 mL, 0.448 mmol) was added, and the mixture was stirred at 160 캜 for 0.5 hour in a sealed vessel. After air-cooling to room temperature, ethyl acetate (5.0 mL) and saturated aqueous ammonium chloride (2.0 mL) were successively added to separate the aqueous layer and the organic layer. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, And distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to give 4- (3-ethoxy-4-ethynyl-5- fluorophenyl) morpholine (60 mg, 54% As a solid.

_{^{1 H-NMR (CDCl 3)}} δ: 6.20 (1H, dd, J = 12.1, 2.2㎐), 6.13 (1H, s), 4.12-4.07 (2H, m), 3.85-3.82 (4H, m), 3.41 (1H, s), 3.20-3.15 (4H, m), 1.46 (3H, t, J = 7.1 Hz). LCMS (ESI) m / z 250 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 34

According to Reference Example 1, using 4- (3-ethoxy-4-ethynyl-5-fluorophenyl) morpholine instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained .

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.77 (1H, s), 7.41-7.36 (1H, m), 6.60 (2H, s), 6.48 (1H, d, J = D, J = 6.4 Hz), 6.42 (1H, s), 5.90 (1H, d, J = 7.0 Hz), 5.37 (1H, m), 4.20 (2H, q, J = 7.0 Hz), 4.12-4.07 (1H, m), 4.06-4.02 (1H, m), 3.74-3.69 (4H, m), 3.27-3.05 , &lt; / RTI &gt; m), 1.36 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 592 [M + H] &lt; ⁺ &gt;.

Reference Example 35

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-4,6-difluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1-ethoxy-2-ethynyl-3,5-difluorobenzene

Ethynyl-1,3,5-trifluorobenzene was used instead of 4- (4-ethynyl-3,5-difluorophenyl) morpholine in accordance with Referential Example 34, Step 1, Compound.

¹ H-NMR (CDCl ₃ )?: 6.48-6.39 (2H, m), 4.09 (2H, q, J = 7.0 Hz), 3.45 (1H, s), 1.47 (3H, t, J = 7.0 Hz).

(Step 2) Reference Example Synthesis of Compound 35

According to Reference Example 1, using 1-ethoxy-2-ethynyl-3,5-difluorobenzene instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.90 (1H, s), 7.36 (1H, s), 7.02-6.97 (2H, m), 6.61-6.58 (2H, m) , 5.92 (1H, d, J = 7.1 Hz), 5.41-5.36 (1H, m), 5.24-5.21 (1H, m), 4.61-4.55 ), 4.11-4.08 (1H, m), 4.07-4.03 (1H, m), 3.25-3.07 (2H, m), 1.38 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 525 [M + H] &lt; ⁺ &gt;.

Reference Example 36

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluorophenyl) prop-1-ynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, the title compound was obtained by using 1-fluoro-2- (prop-2-yn-1-yl) benzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.20 (1H, s), 7.54 (1H, t, J = 8.0㎐), 7.45 (1H, s), 7.33-7.25 (1H, m), 7.20-7.16 ( (1H, m), 7.13-7.08 (1H, m), 5.82 (1H, d, J = 6.8 Hz), 4.80-4.77 (1H, m), 4.30-4.28 m), 3.90 (2H, s), 3.40 - 3.31 (2H, m). LCMS (ESI) m / z 477 [M + H].

Reference Example 37

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-phenyl] thiomorpholine

(Step 1) Synthesis of 4- (4-ethynyl-3,5-difluorophenyl) thiomorpholine

The title compound was obtained by using thiomorpholine instead of morpholine in accordance with Referential Example 23, Step 1.

¹ H-NMR (CDCl ₃ )?: 6.32 (2H, d, J = 11.0 Hz), 3.69-3.66 (4H, m), 3.38 (1H, s), 2.69-2.66 (4H, m). LCMS (ESI) m / z 240 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 37

According to the same manner as in Reference Example 1, using 4- (4-ethynyl-3,5-difluorophenyl) thiomorpholine instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

¹ H-NMR (DMSO-D ₆ )?: 8.18 (1H, s), 7.87 (1H, s), 7.36-7.32 (1H, m), 5.92 (1H, d, J = 7.0 Hz), 5.46-5.32 (1H, m), 5.30-5.16 ), 4.06-4.02 (1H, m), 3.78-3.72 (4H, m), 3.24-3.06 (2H, m), 2.63-2.58 (4H, m). LCMS (ESI) m / z 582 [M + H] &lt; ⁺ &gt;.

Reference Example 38

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro- Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) piperidin-3-ol

The title compound was obtained in the same manner as in Reference Example 23, Step 1, using piperidin-3-ol instead of morpholine.

_{^{1 H-NMR (CDCl 3)}} δ: 6.39 (2H, dt, J = 17.2, 3.2㎐), 3.91-3.83 (1H, m), 3.49 (1H, dd, J = 12.7, 3.4㎐), 3.38 (1H (2H, m), 3.31-3.28 (1H, m), 3.12-3.00 (2H, m), 1.98-1.82 (3H, m), 1.68-1.56 (2H, m). LCMS (ESI) m / z 238 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 38

By using 1- (4-ethynyl-3,5-difluorophenyl) piperidin-3-ol instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.20 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72 (2H, d, J = 12.1㎐), 6.59 (2H , 5.92 (1H, d, J = 7.0 Hz), 5.38 (1H, d, J = M), 3.15-3.07 (IH, m), 3.15-3.07 (IH, m) m), 1.48-1.34 (2H, m), 3.01-2.94 (1H, m), 2.84 (1H, dd, J = 12.6,8.6Hz), 1.89-1.83 m). LCMS (ESI) m / z 580 [M + H] &lt; ⁺ &gt;.

Reference Example 39

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro-4- (3- hydroxyacetidin- Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) azetidin-3-ol

According to Reference Example 23, Step 1, azetidin-3-ol was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 5.90 (2H, dq, J = 19.2, 3.4㎐), 4.83-4.76 (1H, m), 4.17 (2H, dd, J = 8.4, 7.0㎐), 3.75 (2H , dd, J = 8.4, 4.2 Hz), 3.38 (1H, s), 2.21 (1H, d, J = 6.2 Hz). LCMS (ESI) m / z 210 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 39

By using 1- (4-ethynyl-3,5-difluorophenyl) azetidin-3-ol instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, the title compound &Lt; / RTI &gt;

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.85 (1H, s), 7.37-7.32 (1H, m), 6.59 (2H, s), 6.24 (2H, d, J = D, J = 6.4 Hz), 5.91 (1H, d, J = 7.0 Hz), 5.75 ), 4.60-4.54 (2H, m), 4.16-4.07 (3H, m), 4.06-4.02 (1H, m), 3.64 (2H, dd, J = 8.6, 4.6Hz), 3.25-3.17 ), 3.14-3.05 (1 H, m). LCMS (ESI) m / z 552 [M + H] &lt; ⁺ &gt;.

Reference Example 40

Phenyl] ethynyl] -7 - [(2R, 3R) -3-hydroxy-1-piperidyl] 4S, 5R) -3,4-dihydroxy-5- [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of (3R) -1- (4-ethynyl-3,5-difluorophenyl) piperidin-

According to Reference Example 23, Step 1, (R) -piperidin-3-ol was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.39 (2H, d, J = 11.0㎐), 3.91-3.84 (1H, m), 3.49 (1H, dd, J = 12.5, 3.3㎐), 3.38 (1H, s ), 3.33-3.27 (1H, m), 3.12-3.01 (2H, m), 1.98-1.85 (2H, m), 1.80 (1H, d, J = 6.2Hz), 1.69-1.60 (1H, m). LCMS (ESI) m / z 238 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 40

According to Reference Example 1, (3R) -1- (4-ethynyl-3,5-difluorophenyl) piperidin-3-ol was used instead of 2-ethynyl- , The title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72 (2H, d, J = 12.1㎐), 6.59 (2H d, J = 6.4 Hz), 5.92 (1H, d, J = 7.0 Hz), 5.38 (1H, ), 4.57 (1H, dd, J = 12.3, 6.8 Hz), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.68-3.50 (3H, m), 3.23-3.18 ), 3.15-3.07 (1H, m), 3.01-2.94 (1H, m), 2.84 (1H, dd, J = 12.6,8.6Hz), 1.89-1.83 (1H, m), 1.75-1.69 ), 1.47-1.37 (2H, m). LCMS (ESI) m / z 580 [M + H] &lt; ⁺ &gt;.

Reference Example 41

[(2R, 3R, 4S, 5R)] - 3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- - yl] ethynyl] -3,5-difluoro-phenyl] pyrrolidine-3-carboxylic acid

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) pyrrolidine-3-carboxylic acid

The title compound was obtained by using pyrrolidine-3-carboxylic acid instead of morpholine in accordance with Referential Example 23, Step 1.

¹ H-NMR (CDCl ₃ )?: 6.06 (2H, d, J = 10.3 Hz), 3.61-3.52 (2H, m), 3.46-3.25 (4H, m), 2.38-2.33 (2H, m). LCMS (ESI) m / z 252 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 41

According to the same procedure as that described in Reference Example 1, Step 4, l- (4-ethynyl-3,5-difluorophenyl) pyrrolidine-3-carboxylic acid , The title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 12.59 (1H, s), 8.17 (1H, s), 7.85 (1H, s), 7.36-7.32 (1H, m), 6.59 (2H, s), 6.39 (2H, d, J = 11.0 Hz), 5.91 (1H, d, J = 7.0 Hz), 5.38 (1H, m), 4.12-4.08 (1H, m), 4.06-4.02 (1H, m), 3.54-3.42 . LCMS (ESI) m / z 594 [M + H] &lt; ⁺ &gt;.

Reference Example 42

Ethynyl] -7 - [(2R, 3R, 4S, 5R) - (4-amino-5- [2- [2,6-difluoro- Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) piperidin-4-one

According to Reference Example 23, Step 1, piperidin-4-one was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.40 (2H, d, J = 11.0㎐), 3.66 (4H, t, J = 6.0㎐), 3.41 (1H, s), 2.57 (4H, t, J = 6.0 ㎐). LCMS (ESI) m / z 236 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 42

(4-ethynyl-3,5-difluorophenyl) piperidin-4-one was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, To obtain the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.88 (1H, s), 7.37-7.32 (1H, m), 6.86 (2H, d, J = 11.7㎐), 6.60 (2H (1H, m), 5.92 (1H, d, J = 7.0 Hz), 5.40 M), 3.14 (1H, m), 2.44 (4H, t, J = , t, J = 5.9 Hz). LCMS (ESI) m / z 578 [M + H] &lt; ⁺ &gt;.

Reference Example 43

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-dihydro- 4-dihydroxy-5 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) azetidine

According to Reference Example 23, Step 1, azetidine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 5.86 (2H, d, J = 9.5 Hz), 3.93-3.89 (4H, m), 3.37 (1H, s), 2.45-2.37 (2H, m). LCMS (ESI) m / z 194 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 43

(4-ethynyl-3,5-difluorophenyl) azetidine was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4, the title compound was obtained .

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.85 (1H, s), 7.36-7.33 (1H, m), 6.60 (2H, s), 6.20 (2H, d, J = J = 6.4 Hz), 5.22 (1H, d, J = 4.4 Hz), 4.57 (1H, q, J = 6.2 Hz), 5.91 (1H, m), 4.01-4.07 (1H, m), 3.91 (4H, t, J = 7.3 Hz), 3.25-3.17 2.37-2.30 (2 H, m). LCMS (ESI) m / z 536 [M + H] &lt; + &gt;.

Reference Example 44

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-pyridyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 2-ethynylpyridine instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.12 (1H, s), 7.90 (1H, s), 7.78 (1H, t, J = 7.6㎐), 7.60 (1H, d, J = 7.6㎐), Dd, J = 7.6, 5.1 Hz), 7.28 (1H, dd, J = 7.6, 5.1 Hz), 6.53 (2H, s), 5.86 , dd, J = 7.0, 5.7 Hz), 4.04 (1H, dd, J = 5.1, 2.5 Hz), 4.01-3.97 (1H, brm), 3.18-3.02 (2H, m). LCMS (ESI) m / z 446 [M + H] &lt; ⁺ &gt;.

Reference Example 45

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] 2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 1-chloro-2-ethynylbenzene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

¹ H-NMR (DMSO-D ₆ )?: 8.12 (1H, s), 7.88 (1H, s), 7.63-7.52 (1H, m), 7.54-7.53 (1H, m), 7.38-7.32 d, J = 7.6, 5.1 Hz), 6.53 (2H, s), 5.86 (1H, d, J = 7.0 Hz), 4.51 4.03 (1H, dd, J = 5.1, 2.5 Hz), 4.00-3.97 (1H, brm), 3.19-3.02 (2H, m). LCMS (ESI) m / z 479 [M + H] &lt; ⁺ &gt;.

Reference Example 46

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluorophenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynyl-2-fluorobenzene instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.11 (1H, s), 7.86 (1H, s), 7.58 (1H, t, J = 7.6㎐), 7.43-7.37 (1H, m), 7.30-7.26 (2H, m), 7.21 (1H, t, J = 7.6 Hz), 6.52 (2H, s), 5.86 , 4.03 (1H, t, J = 2.5 Hz), 4.00-3.97 (1H, m), 3.17-3.02 (2H, m). LCMS (ESI) m / z 463 [M + H] &lt; ⁺ &gt;.

Reference Example 47

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-methoxyphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethynyl-2-methoxybenzene instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04 (1H, d, J = 8.2㎐), 6.92 (1H d, J = 7.6 Hz), 6.53 (2H, s), 5.84 (1H, d, J = 7.0 Hz), 4.50 5.1, 2.5 Hz), 3.84-3.84 (1H, br m), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m / z 475 [M + H] &lt; ⁺ &gt;.

Reference Example 48

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Dimethylaminophenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, 4-ethynyl-N, N-dimethylaniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04 (1H, d, J = 8.2㎐), 6.92 (1H d, J = 7.6 Hz), 6.53 (2H, s), 5.84 (1H, d, J = 7.0 Hz), 4.50 5.1, 2.5 Hz), 3.84-3.84 (1H, br m), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m / z 475 [M + H] &lt; ⁺ &gt;.

Reference Example 49

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] ] Tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, the title compound was obtained by using 2-ethynyl benzonitrile instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.12 (1H, s), 7.93 (1H, s), 7.87 (1H, d, J = 7.5㎐), 7.74-7.68 (2H, m), 7.52 (1H dt, J = 1.4, 7.5 Hz), 7.29 (1H, m), 6.53 (2H, s), 5.87 (1H, d, J = 6.8 Hz), 5.40 , 4.53 (1H, t, J = 5.5 Hz), 4.04 (2H, dd, J = 5.5, 2.7 Hz), 4.01-3.98 (2H, brm), 3.19-3.03 (2H, m). LCMS (ESI) m / z 470 [M + H] &lt; ⁺ &gt;.

Reference Example 50

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] 2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 1, Step 4, using prop-2-yn-1-yl cyclohexane instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.05 (1H, s), 7.56 (1H, s), 7.27 (1H, dd, J = 7.5, 4.1㎐), 6.51 (2H, s), 5.79 (1H d, J = 6.8 Hz), 4.46 (1H, dd, J = 6.8,5.5 Hz), 4.01 (1H, dd, J = 5.5, 2.1 Hz), 3.97-3.94 (1H, brm), 3.17-2.99 2H, m), 2.32 (2H, d, J = 6.2 Hz), 1.76-1.72 (2H, brm), 1.65-1.60 (2H, brm), 1.58-1.54 brm), 1.23-0.93 (5H, m). LCMS (ESI) m / z 465 [M + H] &lt; ⁺ &gt;.

Reference Example 51

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-methoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-ethynyl-1-fluoro-3-methoxybenzene

2-fluoro-6-methoxybenzaldehyde (2.0 g, 13 mmol) was dissolved in methanol (20 mL), and potassium carbonate (3.6 g, 26 mmol) and dimethyl (1-diazo- Phosphonate (2.3 mL, 16 mmol) was added, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Ethyl acetate, a saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction solution, and the organic layer was washed with saturated brine. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 2-ethynyl-1-fluoro-3-methoxybenzene (1.6 g, 11 mmol, 81%) as a reddish brown solid.

_{^{1 H-NMR (CDCl 3)}} δ: 7.31-7.22 (1H, m), 6.76-6.65 (2H, m), 3.92 (3H, s), 3.53 (1H, s).

(Step 2) Reference Example Synthesis of Compound 51

Ethynyl-1-fluoro-3-methoxybenzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.57 (1H, s), 7.37-7.30 (1H, m), 6.90 (1H, d, J = 8.5㎐), 6.82-6.78 ( (1H, m), 5.86 (1H, d, J = 6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.27 , 3.40-3.35 (2H, m). LCMS (ESI) m / z 493 [M + H] &lt; ⁺ &gt;.

Reference Example 52

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfa Methylamino] methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 5- (benzyloxy) -2-ethynylpyridine

According to Reference Example 51, Step 1, 5- (benzyloxy) picoline aldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 8.36 (1H, d, J = 2.9㎐), 7.44-7.34 (5H, m), 7.20 (2H, dd, 8.8, 2.9㎐), 5.13 (2H, s), 3.07 (1 H, s). LCMS (ESI) m / z 210 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 52

According to Reference Example 1, Step 4, 5- (benzyloxy) -2-ethynylpyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.29 (1H, d, J = 2.9㎐), 8.22 (1H, s), 7.65 (1H, s), 7.56 (1H, d, J = 8.0㎐), 7.50 (2H, m), 3.40-3.30 (2H, m), 5.30 (2H, , m). LCMS (ESI) m / z 552 [M + H] &lt; ⁺ &gt;.

Reference Example 53

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [ (Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4- (benzyloxy) -1-ethynyl-2-methoxybenzene

According to Reference Example 51, Step 1, using 4- (benzyloxy) -2-methoxybenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.48-7.32 (6H, m), 6.50-6.55 (2H, m), 5.07 (2H, s), 3.87 (3H, s), 3.24 LCMS (ESI) m / z 239 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 53

According to Reference Example 1, Step 4, 4- (benzyloxy) -1-ethynyl-2-methoxybenzene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.16 (1H, s), 7.74 (1H, s), 7.46-7.32 (7H, m), 6.78-6.76 (1H, brs), 6.67 (1H, d, J = 8.0 Hz), 6.63-6.59 (2H, br s), 5.90 (1H, d, J = 6.3 Hz), 5.39 , 3.16-4.04 (1H, m), 3.89 (3H, s), 3.26-3.15 (1H, m), 5.16 (2H, s), 4.61-4.55 , 3.15-3.03 (1H, m). LCMS (ESI) m / z 581 [M + H] &lt; ⁺ &gt;.

Reference Example 54

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy- 5 - [(Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3,5-difluorophenol

According to Reference Example 51, Step 1, 2,6-difluoro-4-hydroxybenzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to give the title compound.

¹ H-NMR (CDCl ₃ )?: 6.43 (2H, d, J = 8.0 Hz), 5.60-5.40 (1H, brs), 3.42 (1H, s).

(Step 2) Reference Example Synthesis of Compound 54

According to Reference Example 1, Step 4, 4-ethynyl-3,5-difluorophenol was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.58 (1H, s), 6.48 (2H, d, J = 9.5㎐), 5.86 (1H, d, J = 6.8㎐), 4.85 -4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23 (1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m / z 497 [M + H] &lt; ⁺ &gt;.

Reference Example 55

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-ethoxy-6-fluorobenzaldehyde

2-fluoro-6-hydroxybenzaldehyde (50 g, 360 mmol) was dissolved in N, N-dimethylformamide (500 mL) and potassium carbonate (74 g, 540 mmol) and iodoethane (86 mL, 1.1 mol) And the mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution to obtain a layer, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 2-ethoxy-6-fluorobenzaldehyde (59 g, 98%) as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ: 10.47 (1H, s), 7.50-7.41 (1H, m), 6.77-6.67 (2H, m), 4.16 (2H, q, J = 6.8㎐), 1.48 (3H , t, J = 6.8 Hz). LCMS (ESI) m / z 169 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 1-ethoxy-2-ethynyl-3-fluorobenzene

According to the procedure of Reference Example 51, Step 1, using 2-ethoxy-6-fluorobenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.28-7.20 (1H, m), 6.74-6.63 (2H, m), 4.13 (2H, q, J = 7.1㎐), 3.50 (1H, s), 1.47 (3H , t, J = 7.1 Hz).

(Step 3) Reference Example Synthesis of Compound 55

Ethynyl-3-fluorobenzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.58 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J = 8.0㎐), 6.82-6.74 ( M), 5.86 (1H, d, J = 7.0 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.21 m), 1.47 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 507 [M + H] &lt; ⁺ &gt;.

(Step 4) Synthesis of 4-amino-7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Synthesis of [2- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine hydrochloride

The title compound hydrochloride was obtained in accordance with Referential Example 1, Step 5.

^{1 H-NMR (DMSO-D} 6) δ: 8.38 (1H, s), 8.13 (1H, s), 7.44-7.38 (1H, m), 7.01-6.91 (3H, m), 6.80-6.40 (1H, (2H, q, J = 7.0 Hz), 6.01 (1H, d, J = 6.8 Hz), 4.51-4.48 (1H, m), 4.24 m), 3.24-3.19 (1H, m), 3.14-3.09 (1H, m), 1.38 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 507 [M + H] &lt; ^{+ &}

Reference Example 56

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-isopropoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-fluoro-6-isopropoxybenzaldehyde

According to Reference Example 55, Step 1, 2-iodopropane was used instead of iodoethane to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 10.44 (1H, s), 7.44 (1H, dt, J = 6.3, 8.5㎐), 6.77 (1H, d, J = 8.5㎐), 6.68 (1H, dd, J = 10.2, 8.5 Hz), 4.72-4.62 (1H, m), 1.41 (6H, d, J = 6.1 Hz).

(Step 2) Synthesis of 2-ethynyl-1-fluoro-3-isopropoxybenzene

According to Reference Example 51, Step 1, 2-fluoro-6-isopropoxybenzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.22 (1H, dt, J = 6.6, 8.4㎐), 6.71-6.65 (2H, m), 4.64-4.56 (1H, m), 3.47 (1H, s), 1.39 (6H, d, J = 6.2 Hz).

(Step 3) Reference Example Synthesis of Compound 56

Ethynyl-1-fluoro-3-isopropoxybenzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

¹ H-NMR (CD ₃ OD)?: 8.24 (1H, s), 7.57 (1H, s), 7.32-7.26 (1H, m), 6.89 (1H, m), 5.87 (1H, d, J = 6.8 Hz), 4.85-4.81 (1H, m), 4.79-4.71 m), 3.42-3.33 (2H, m), 1.41 (6H, d, J = 5.9 Hz). LCMS (ESI) m / z 521 [M + H] &lt; ⁺ &gt;.

Reference Example 57

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-isoquinolin- 5 - [(Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3,5-difluorobenzonitrile

According to Reference Example 51, Step 1, 3,5-difluoro-4-formylbenzonitrile was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 7.25 (2H, d, J = 8.0 Hz), 3.73 (1H, s).

(Step 2) Reference Example Synthesis of Compound 57

According to Reference Example 1, Step 4, 4-ethynyl-3,5-difluorobenzonitrile was used instead of 2-ethynyl-1,3-difluorobenzene to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.26 (1H, s), 7.78 (1H, s), 7.58 (2H, d, J = 7.1㎐), 5.88 (1H, d, J = 6.8㎐), 4.85 M), 4.27-4.24 (1H, m), 3.42-3.33 (2H, m). LCMS (ESI) m / z 506 [M + H] &lt; ⁺ &gt;.

Reference Example 58

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-benzoate

(Step 1) Synthesis of methyl 4-ethynyl-3,5-difluorobenzimidate

(200 mg, 1.2 mmol) was dissolved in methanol (3 mL), potassium carbonate (331 mg, 2.4 mmol) and dimethyl (1-diazo Oxopropyl) phosphonate (0.22 mL, 1.4 mmol) was added thereto, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 2 hours and 30 minutes. Ethyl acetate, a saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction solution, and the organic layer was washed with saturated brine. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain methyl 4-ethynyl-3,5-difluorobenzimidate (172 mg ).

LCMS (ESI) m / z 196 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 58

According to Reference Example 1, Step 4, methyl 4-ethynyl-3,5-difluorobenzimidate was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.27 (1H, s), 7.76 (1H, s), 7.69 (2H, d, J = 7.8㎐), 5.88 (1H, d, J = 6.6㎐), 4.85 (1H, m), 4.74 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 3.94 (3H, s), 3.42-3.33 (2H, LCMS (ESI) m / z 539 [M + H] &lt; ⁺ &gt;.

Reference Example 59

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of (2-ethynyl-3-fluorophenyl) (methyl) sulfan

Fluoro-6- (methylthio) benzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde according to Reference Example 51, Step 1, to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.32-7.25 (1H, m), 6.94 (1H, d, J = 8.1㎐), 6.89-6.64 (1H, m), 3.70 (1H, s), 2.51 (3H , s).

(Step 2) Reference Example Synthesis of Compound 59

The title compound was obtained by using (2-ethynyl-3-fluorophenyl) (methyl) sulfane instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.65 (1H, s), 7.37-7.31 (1H, m), 7.11 (1H, d, J = 8.0㎐), 6.99-6.94 ( (1H, m), 5.88 (1H, d, J = 6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.31 m), 2.56 (3H, s). LCMS (ESI) m / z 509 [M + H] &lt; ⁺ &gt;.

Reference Example 60

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-propoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-fluoro-6-propoxybenzaldehyde

According to Reference Example 55, Step 1, 1-iodopropane was used instead of iodoethane to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 10.48 (1H, s), 7.46 (1H, dt, J = 6.3, 8.5㎐), 6.76 (1H, d, J = 8.5㎐), 6.71 (1H, dd, J = 10.4, 8.5 Hz), 4.04 (2H, t, J = 6.3 Hz), 1.93-1.83 (2H, m), 1.56 (1H, s), 1.07 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 183 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethynyl-1-fluoro-3-propoxybenzene

According to Reference Example 51, Step 1, 2-fluoro-6-propoxybenzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.27-7.20 (1H, m), 6.72-6.63 (2H, m), 4.01 (2H, t, J = 6.5㎐), 3.49 (1H, s), 1.81-1.91 (2H, m), 1.07 (3H, t, J = 8.0 Hz).

(Step 3) Reference Example Synthesis of Compound 60

Ethynyl-1-fluoro-3-propoxybenzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.57 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J = 8.0㎐), 6.80-6.74 ( (1H, m), 5.86 (1H, d, J = 6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.31 J = 6.7 Hz), 3.42-3.33 (2H, m), 1.92-1.82 (2H, m), 1.07 (3H, t, 7.4 Hz). LCMS (ESI) m / z 521 [M + H] &lt; ⁺ &gt;.

Reference Example 61

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6- (2,2,2-trifluoroethoxy) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-fluoro-6- (2,2,2-trifluoroethoxy) benzaldehyde

According to Reference Example 55, Step 1, 1,1,1-trifluoro-2-iodoethane was used instead of iodoethane to give the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 10.45 (1H, s), 7.53 (1H, dt, J = 6.1, 8.6㎐), 6.89 (1H, dd, J = 9.8, 8.6㎐), 6.77 (1H, d , J = 8.6 Hz), 4.48 (2H, q, J = 8.0 Hz). LCMS (ESI) m / z 223 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethynyl-1-fluoro-3- (2,2,2-trifluoroethoxy) benzene

Fluoro-6- (2,2,2-trifluoroethoxy) benzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde according to Reference Example 51, Step 1, the title compound was obtained .

¹ H-NMR (CDCl ₃ )?: 7.32-7.24 (1H, m), 6.88-6.81 (1H, m), 6.72 ), 3.53 (1H, s).

(Step 3) Reference Example Synthesis of Compound 61

Ethyl-1-fluoro-3- (2,2,2-trifluoroethoxy) benzene was used instead of 2-ethynyl-1,3-difluorobenzene in accordance with Referential Example 1, , The title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.60 (1H, s), 7.39-7.33 (1H, m), 6.98 (1H, d, J = 8.5㎐), 6.93-6.89 ( (1H, m), 5.86 (1H, d, J = 7.1 Hz), 4.84-4.82 (1H, m), 4.76 (1 H, m), 3.40-3.37 (2 H, m). LCMS (ESI) m / z 561 [M + H] &lt; ⁺ &gt;.

Reference Example 62

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-methoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2-ethoxy-6-methoxybenzaldehyde

According to Reference Example 55, Step 1, using 2-hydroxy-6-methoxybenzaldehyde instead of 2-fluoro-6-hydroxybenzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 10.53 (1H, s), 7.42 (1H, t, J = 8.5㎐), 6.56 (2H, d, J = 8.5㎐), 4.15-4.08 (2H, q, J = 7.0 Hz), 3.90 (3H, s), 1.46 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 181 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 1-ethoxy-2-ethynyl-3-methoxybenzene

According to Reference Example 51, Step 1, using 2-ethoxy-6-methoxybenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.23 (1H, t, J = 8.4㎐), 6.55-6.50 (2H, m), 4.12 (2H, q, J = 7.0㎐), 3.90 (3H, s), 3.53 (1H, s), 1.46 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 177 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 62

According to Reference Example 1, Step 4, the title compound was obtained by using 1-ethoxy-2-ethynyl-3-methoxybenzene instead of 2-ethynyl-1,3-difluorobenzene.

¹ H-NMR (CD ₃ OD)?: 8.22 (1H, s), 7.48 (1H, s), 7.27-7.23 (1H, m), 6.67-6.64 M), 4.18 (2H, q, J = 7.0 Hz), 3.91 (3H, s) , 3.42-3.31 (2H, m), 1.45 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 519 [M + H] &lt; ⁺ &gt;.

Reference Example 63

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] -7-methoxyquinoline

(Step 1) Synthesis of 8-ethynyl-7-methoxyquinoline

According to Reference Example 51, Step 1, 7-methoxyquinoline-8-carbaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 9.03 (1H, dd, J = 4.2, 1.8㎐), 8.12 (1H, dd, J = 8.3, 1.8㎐), 7.83 (1H, d, J = 9.2㎐), 7.35 (1H, d, J = 9.2 Hz), 7.33 (1H, dd, J = 8.3, 4.2 Hz), 4.10 (3H, s), 3.87 (1H, s). LCMS (ESI) m / z 184 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 63

According to Reference Example 1, Step 4, 8-ethynyl-7-methoxyquinoline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.92 (1H, dd, J = 4.3, 1.7㎐), 8.29 (1H, dd, J = 8.3, 1.7㎐), 8.22 (1H, s), 7.92 (1H, d, J = 9.0 Hz), 7.59 (1H, s), 7.54 (1H, d, J = 9.0 Hz), 7.43 (1H, m), 4.61-4.59 (1H, m), 4.33 (1H, dd, J = 5.4,2.7 Hz), 4.29-4.26 . LCMS (ESI) m / z 526 [M + H] &lt; ⁺ &gt;.

Reference Example 64

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-

(Step 1) Synthesis of 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

(1.50 g, 9.79 mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (2.98 g, 21.5 mmol) and methyl iodide (1.67 g, 11.8 mmol) were added thereto. After stirring at room temperature for 3 days, water (60 mL) and ethyl acetate (60 mL) were added successively to separate an aqueous layer and an organic layer, and then they were collected. The aqueous layer was extracted with ethyl acetate (60 mL), and the obtained organic layers were combined. The organic layer was washed sequentially with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (1.09 g) Water.

¹ H-NMR (CDCl ₃ )?: 6.58-6.51 (3H, m), 4.31 (2H, t, J = 4.4 Hz), 3.20 (2H, t, J = 4.4 Hz), 2.84 (3H, s). LCMS (ESI) m / z 168.1 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde

Methyl-2,3-dihydro-1,4-benzoxazine (1.07 g, 6.40 mmol) was dissolved in tetrahydrofuran (17.1 mL) -Butyllithium (1.6 M hexane solution, 4.83 mL) was added dropwise. After stirring at -78 占 폚 for 3 hours, N, N-dimethylformamide (702 mg, 9.60 mmol) was added dropwise and the temperature was raised to 0 占 폚. A saturated aqueous ammonium chloride solution (40 mL) and ethyl acetate (40 mL) were added successively, and each was collected. The aqueous layer was extracted twice with ethyl acetate (40 mL), and the obtained organic layers were combined. The organic layer was washed successively with saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde ( 1.13 g) as a light yellow solid.

_{^{1 H-NMR (CDCl 3)}} δ: 10.38 (1H, d, J = 2.2㎐), 6.78-6.73 (1H, m), 6.62-6.57 (1H, m), 4.45-4.42 (2H, m), 3.28 -3.25 (2H, m), 2.87 (3H, d, J = 1.8 Hz). LCMS (ESI) m / z 196.2 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

Fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde instead of 2-fluoro-6-methoxybenzaldehyde was obtained in the same manner as in Reference Example 51, , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 6.59-6.56 (2H, m), 4.43 (2H, t, J = 4.4㎐), 3.49 (1H, s), 3.22 (2H, t, J = 4.4㎐), 2.84 (3 H, s). LCMS (ESI) m / z 192.4 [M + H] &lt; ^{+ &}

(Step 4) Reference Example Synthesis of Compound 64

According to Reference Example 1, Step 4, 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzo Oxazine, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.88 (1H, s), 7.38 (1H, dd, J = 7.3, 4.8㎐), 6.78-6.69 (2H, m), 6.60 (2H, s), 5.91 (1H, d, J = 7.3 Hz), 5.40 (1H, s), 5.24 J = 4.2 Hz), 4.12-4.07 (1H, m), 4.07-4.02 (1H, m), 3.26 (2H, t, J = 4.2 Hz), 3.23-3.16 , &lt; / RTI &gt; m), 2.82 (3H, s). LCMS (ESI) m / z 534.3 [M + H] &lt; ⁺ &gt;.

(Step 5) 8- [2- [4-Amino-7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine hydrochloride

The title compound hydrochloride was obtained in accordance with Referential Example 1, Step 5.

^{1 H-NMR (DMSO-D} 6) δ: 8.47 (1H, s), 8.23 (1H, s), 6.82-6.76 (2H, m), 6.06 (1H, d, J = 6.8㎐), 4.49-4.45 (3H, m), 4.12 (1H, dd, J = 5.2, 2.8 Hz), 4.05 (1H, dt, J = 5.6, 2.8 Hz), 3.28 dd, J = 14.0, 6.0 Hz), 3.13 (1H, dd, J = 14.0, 6.0 Hz), 2.84 (3H, s). LCMS (ESI) m / z 534.3 [M + H] &lt; ^{+ &}

Reference Example 65

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,4-dimethoxy-3-pyridyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 3-ethynyl-2,4-dimethoxypyridine

According to Reference Example 51, Step 1, 2,4-dimethoxy nicotinaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 8.05 (1H, d, J = 6.1㎐), 6.54 (1H, d, J = 6.1㎐), 4.02 (3H, s), 3.95 (3H, s), 3.58 ( 1H, s). LCMS (ESI) m / z 164 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 65

According to Reference Example 1, Step 4, 3-ethynyl-2,4-dimethoxypyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 8.08 (1H, d, J = 6.1㎐), 7.85 (1H, d, J = 2.0㎐), 7.35 (1H, s), (1H, d, J = 7.1 Hz), 6.89 (1H, d, J = 6.1 Hz), 6.59 ), 4.06-4.03 (1H, m), 3.95 (6H, d, J = 2.7Hz), 3.35 (2H, s), 3.22-3.10 (2H, m). LCMS (ESI) m / z 506 [M + H] &lt; ⁺ &gt;.

Reference Example 66

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Ethylsulfanyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2- (ethylthio) -6-fluorobenzaldehyde

N-Butyl lithium (2.69 M hexane solution, 5.71 mL) was added dropwise at -78 째 C under cooling and stirring, to a solution of . After stirring at -78 ° C for 30 minutes, N, N-dimethylformamide (2.95 mL, 38.4 mmol) was added and the mixture was stirred for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to give 2- (ethylthio) -6-fluorobenzaldehyde (430 mg, 18%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ )?: 10.52 (1H, s), 7.51-7.46 (1H, m), 7.13 (1H, d, J = 8.8 Hz) 2.99 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz).

(Step 2) Synthesis of ethyl (2-ethynyl-3-fluorophenyl) sulfane

According to Reference Example 51, Step 1, using 2- (ethylthio) -6-fluorobenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.30-7.24 (1H, m), 7.03 (1H, d, J = 8.1㎐), 6.89 (1H, dd, J = 8.8, 8.1㎐), 3.71 (1H, s ), 3.03 (2H, q, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz).

(Step 3) Reference Example Synthesis of Compound 66

According to Reference Example 1, Step 4, ethyl (2-ethynyl-3-fluorophenyl) sulfane was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.16 (1H, s), 7.95 (1H, s), 7.91 (1H, d, J = 7.0㎐), 7.46 (1H, t, J = 7.7㎐), (2H, m), 7.22 (1H, d, J = 8.1 Hz), 7.12 (1H, t, J = 8.8 Hz), 6.57 ), 5.37 (1H, brs), 5.21 (1H, brs), 4.57 (1H, brs), 4.09-4.06 (1H, brm), 4.04-4.01 (1H, brm), 3.23-3.05 1.28 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 523 [M + H] &lt; ⁺ &gt;.

Reference Example 67

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-difluoro-4- (triazol-2-ylmethoxy) Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4 - ((2H-1,2,3-triazol-2-yl) methoxy) -2,6-difluorobenzaldehyde

According to Reference Example 55, Step 1, 2,6-difluoro-4-hydroxybenzaldehyde was used instead of 2-fluoro-6-hydroxybenzaldehyde and 2- (chloromethyl) triazole was used instead of iodoethane To obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 10.21 (1H, s), 7.76 (2H, s), 6.88 (2H, d, J = 10.0 Hz), 6.30 (2H, s). LCMS (ESI) m / z 240 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2 - ((4-ethynyl-3,5-difluorophenoxy) methyl) -2H-1,2,3-triazole

According to Reference Example 51, Step 1, 4 - ((2H-1,2,3-triazol-2-yl) methoxy) -2,6-difluoro Benzaldehyde, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.74 (2H, s), 7.26 (2H, s), 6.82 (1H, d, J = 8.5 Hz), 6.24 (1H, s), 3.43 LCMS (ESI) m / z 236 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 67

According to Reference Example 1, Step 4, 2 - ((4-ethynyl-3,5-difluorophenoxy) methyl) -2H-1, 2,3-triazole, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.99 (2H, s), 7.96 (1H, s), 7.36-7.31 (1H, brs), 7.19 (2H, d, J = (2H, s), 5.91 (1H, d, J = 7.1 Hz), 5.40 (1H, d, J = 6.6 Hz), 5.23 J = 4.1 Hz), 4.59-4.54 (1H, m), 4.10-4.06 (1H, m), 4.05-4.02 (1H, m), 3.22-3.16 . LCMS (ESI) m / z 578 [M + H] &lt; ⁺ &gt;.

Reference Example 68

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2- (ethylamino) -6-fluoro-phenyl] ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 2- (ethylamino) -6-fluorobenzaldehyde

According to Reference Example 23, Step 1, the title compound was obtained by using 2-ethynyl-1,3,5-trifluorobenzene and 2,6-difluorobenzaldehyde and ethylamine instead of morpholine.

¹ H-NMR (CDCl ₃ )?: 10.28 (1H, s), 8.66 (1H, brs), 7.35-7.29 (1H, m), 6.45 , J = 11.4, 8.1 Hz), 3.32-3.25 (2H, m), 1.33 (3H, t, J = 7.3 Hz). LRMS (ESI) m / z 168 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of N-ethyl-2-ethynyl-3-fluoroaniline

According to the procedure of Reference Example 51, Step 1, using 2- (ethylamino) -6-fluorobenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.13 (1H, dd, J = 14.7, 7.7㎐), 6.38-6.34 (2H, m), 4.62-4.56 (1H, brm), 3.62 (1H, s), 3.21 (2H, d, J = 7.3, 6.6 Hz), 1.29 (3H, t, J = 7.3 Hz). LRMS (ESI) m / z 164 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 68

Ethyl-2-ethynyl-3-fluoroaniline was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.22 (1H, s), 7.55 (1H, s), 7.26 (1H, ddd, J = 8.4, 8.4, 7.0㎐), 6.82 (1H, d, J = 8.4 (1H, d, J = 5.5, 2.6 Hz), 6.74 (1H, t, J = 8.4 Hz), 5.87 (2H, m), 1.46 (3H, t, J = 7.0 Hz), 4.23-4.17 (2H, m), 4.19 (1H, q, J = 7.0 Hz). LCMS (ESI) m / z 506 [M + H] &lt; ⁺ &gt;.

Reference Example 69

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [(Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 3-ethynyl-2,4-difluoropyridine

According to Reference Example 51, Step 1, 2,4-difluoronicotine aldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

¹ H-NMR (ACETONE-D ₆ ) ?: 8.38 (1H, dd, J = 8.2, 5.7 Hz), 7.44-7.40 (1H, m), 4.46 (1H, s). LCMS (ESI) m / z 140 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 69

According to Reference Example 1, Step 4, 3-ethynyl-2,4-difluoropyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 8.18 (1H, dd, J = 8.2, 5.8㎐), 7.73 (1H, s), 7.27 (1H, dd, J = 8.2, 5.8 D, J = 5.5, 2.6 Hz), 4.26 (1H, q, J = 3.1Hz), 5.87 (1H, d, J = 6.6Hz), 4.82 ㎐), 3.43-3.33 (2H, m). LCMS (ESI) m / z 482 [M + H] &lt; ⁺ &gt;.

Reference Example 70

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Ethylsulfonyl-6-fluoro-4-pyrrolidin-l-yl-phenyl) ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 2,6-difluoro-4- (pyrrolidin-1-yl) benzaldehyde

The title compound was obtained according to Referential Example 23, Step 1 by using 2-ethynyl-1,3,5-trifluorobenzene and 2,4,6-trifluorobenzaldehyde and pyrrolidine instead of morpholine. .

¹ H-NMR (CDCl ₃ )?: 10.04 (1H, s), 6.01 (2H, d, J = 12.8 Hz), 3.35-3.32 (4H, m), 2.07-2.03 (4H, m). LCMS (ESI) m / z 212 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2- (ethylthio) -6-fluoro-4- (pyrrolidin-1-yl) benzaldehyde

(3.7g, 18mmol) was dissolved in N, N-dimethylformamide (37mL) and sodium ethanethiolate (1.6g, 18mmol) was added dropwise to a solution of 2, 6-difluoro-4- (pyrrolidin- ), And the mixture was stirred at room temperature for 30 minutes. To the reaction solution were added ethyl acetate, water and a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: chloroform) to give 2- (ethylthio) -6-fluoro-4- (pyrrolidin-1-yl) benzaldehyde (4.4 g) as a white solid .

_{^{1 H-NMR (CDCl 3)}} δ: 10.18 (1H, s), 6.10 (1H, d, J = 2.0㎐), 5.98 (1H, dd, J = 14.3, 2.0㎐), 3.39-3.35 (4H, m ), 2.91 (2H, q, J = 7.3 Hz), 2.07-2.04 (4H, m), 1.41 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 254 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 2- (ethylsulfonyl) -6-fluoro-4- (pyrrolidin-1-yl) benzaldehyde

(79 mg, 0.31 mmol) was dissolved in dichloromethane (1.6 mL), and 3-chloro-benzoic acid (110 mg, Mg, 0.65 mmol) were added, and the mixture was stirred for 2 hours in an ice bath. 3-Chlorobenzoic acid (56 mg, 0.32 mmol) was added in an ice bath, and the mixture was stirred for 1 hour in an ice bath. Then, 3-chloroperbenzoic acid (10 mg, 0.058 mmol) was further added in an ice bath and stirred for 30 minutes in an ice bath. To the reaction solution was added chloroform, water and a saturated aqueous sodium hydrogencarbonate solution in an ice bath, and the aqueous layer was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give 2- (ethylsulfonyl) -6-fluoro-4- (pyrrolidin- 1 -yl) benzaldehyde (54 mg, 0.19 mmol, 62%) as a yellow solid.

_{^{1 H-NMR (CDCl 3)}} δ: 10.28 (1H, s), 7.19 (1H, d, J = 2.6㎐), 6.33 (1H, dd, J = 13.9, 2.6㎐), 3.62 (2H, q, J = 7.5 Hz), 3.50-3.40 (4H, m), 2.11-2.08 (4H, m), 1.31 (3H, t, J = 7.5 Hz). LCMS (ESI) m / z 286 [M + H] &lt; ^{+ &}

(Step 4) Synthesis of 1- (3- (ethylsulfonyl) -4-ethynyl-5-fluorophenyl) pyrrolidine

(Ethylsulfonyl) -6-fluoro-4- (pyrrolidin-1-yl) benzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde according to Reference Example 51, The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.01 (1H, d, J = 2.3㎐), 6.38 (1H, dd, J = 11.9, 2.3㎐), 3.63 (1H, s), 3.49 (2H, q, J = 7.4 Hz), 3.36-3.32 (4H, m), 2.07-2.04 (4H, m), 1.27 (3H, t, J = 7.4 Hz). LCMS (ESI) m / z 282 [M + H] &lt; ^{+ &}

(Step 5) Reference Example Synthesis of Compound 70

(3- (ethylsulfonyl) -4-ethynyl-5-fluorophenyl) pyrrolidine was used instead of 2-ethynyl-1,3-difluorobenzene in accordance with Referential Example 1, , The title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.22 (1H, s), 7.61 (1H, s), 7.01 (1H, d, J = 2.3㎐), 6.66 (1H, dd, J = 12.4, 2.3㎐) , 5.86 (1H, d, J = 7.1 Hz), 4.85-4.81 (1H, m), 4.32-4.30 (1H, m), 4.27-4.24 ), 3.40-3.36 (4H, m), 3.31-3.30 (2H, m), 2.10-2.07 (4H, m), 1.25 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 624 [M + H].

Reference Example 71

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 3-fluoro-5-methoxy-4-pyridyl) ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3-fluoro-5-methoxypyridine

According to Reference Example 51, Step 1, 3-fluoro-5-methoxyisonicotinaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 8.21-8.17 (2H, m), 4.03 (3H, s), 3.69 (1H, s). LCMS (ESI) m / z 152 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 71

According to Reference Example 1, Step 4, 4-ethynyl-3-fluoro-5-methoxypyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.38 (1H, d, J = 7.8㎐), 8.37 (1H, s), 8.20 (1H, s), 8.05 (1H, s), 7.32-7.29 (1H (1H, brs), 6.58 (2H, s), 5.93 (1H, d, J = 6.8 Hz), 5.41-5.38 (1H, brs), 5.23-5.21 4.08-4.04 (2H, m), 4.07 (3H, s), 3.22-3.18 (1H, m), 3.12-3.08 (1H, m). LCMS (ESI) m / z 494 [M + H].

Reference Example 72

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethylsulfonyl-6-fluoro-4 - [(3R) -3-hydroxypyrrolidin- 1 -yl] phenyl] ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 2,6-difluoro-4 - [(3R) -3-hydroxypyrrolidin-1-yl) benzaldehyde

According to Reference Example 23, Step 1, 2-ethynyl-1,3,5-trifluorobenzene and 2,4,6-trifluorobenzaldehyde instead of morpholine, (R) -pyrrolidin- Ol, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 10.05 (1H, s), 6.03 (2H, d, J = 12.4㎐), 4.70-4.66 (1H, m), 3.60-3.53 (2H, m), 3.48-3.42 (1H, m), 3.36-3.31 (1H, m), 2.21-2.12 (2H, m), 1.79 (1H, d, J = 3.9 Hz). LCMS (ESI) m / z 228 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethylsulfanyl-6-fluoro-4 - [(3R) -3-hydroxypyrrolidin-1-yl) benzaldehyde

According to Reference Example 70, Step 2, 2,6-difluoro-4 - [(3R) -3-hydroxypyridazinone was used instead of 2,6-difluoro-4- (pyrrolidin- Piperidin-1-yl) benzaldehyde, the titled compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 10.19 (1H, s), 6.11 (1H, d, J = 2.2㎐), 6.00 (1H, dd, J = 14.1, 2.2㎐), 4.69-4.66 (1H, m (2H, m), 3.63-3.57 (2H, m), 3.50-3.45 (1H, m), 3.41-3.35 1.77 (1H, d, J = 4.1 Hz), 1.41 (3H, t, J = 7.4 Hz). LCMS (ESI) m / z 270 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 2-ethylsulfonyl-6-fluoro-4 - [(3R) -3-hydroxypyrrolidin-1-yl) benzaldehyde

Ethylsulfanyl-6-fluoro-4 - [((ethylthio) -6-fluoro-4- (pyrrolidin- 1 -yl) benzaldehyde was obtained in the same manner as in Reference Example 70, 3R) -3-hydroxypyrrolidin-1-yl) benzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 10.30 (1H, s), 7.20 (1H, d, J = 2.4㎐), 6.36 (1H, dd, J = 14.0, 2.4㎐), 4.73-4.71 (1H, m ), 3.67-3.42 (4H, m), 3.46-3.42 (1H, m), 3.35-3.32 (1H, m), 2.21-2.17 1.32 (3H, t, J = 7.6 Hz). LCMS (ESI) m / z 302 [M + H] &lt; ^{+ &}

(Step 4) Synthesis of (3R) -1- (3- (ethylsulfonyl) -4-ethynyl-5-fluorophenyl) pyrrolidin-

According to Reference Example 51, Step 1, 2-ethylsulfonyl-6-fluoro-4 - [(3R) -3-hydroxypyrrolidin- ) Benzaldehyde, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.03 (1H, d, J = 2.4 Hz), 6.41 (1H, dd, J = 11.7, 2.4 Hz), 4.69-4.67 (2H, m), 1.69 (1H, d, J = 3.7 Hz), 1.27 (3H, t, J = 7.4 Hz). LCMS (ESI) m / z 298 [M + H] &lt; ^{+ &}

(Step 5) Reference Example Synthesis of Compound 72

(3R) -1- (3- (Ethylsulfonyl) -4-ethynyl-5-fluorophenyl) -4-methylpyrrolidine was obtained in the same manner as in Reference Example 1, Pyrrolidin-3-ol, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.62 (1H, s), 7.01 (1H, d, J = 2.3㎐), 6.67 (1H, dd, J = 12.2, 2.3㎐) (1H, m), 5.87 (1H, d, J = 7.1 Hz), 4.85-4.79 (1H, m), 4.58-4.54 (1H, m), 4.32-4.30 M), 2.42 (1H, m), 2.42-2.14 LCMS (ESI) m / z 640 [M + H].

Reference Example 73

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [ Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1-chloro-2-ethynyl-3-fluorobenzene

According to the procedure of Reference Example 51, Step 1, using 2-chloro-6-fluorobenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.29-7.21 (2H, m), 7.05-7.00 (1H, m), 3.61 (1H, s).

(Step 2) Reference Example Synthesis of Compound 73

Chloro-2-ethynyl-3-fluorobenzene instead of 2-ethynyl-1,3-difluorobenzene in accordance with Referential Example 1, Step 4, the title compound was obtained.

¹ H-NMR (CD ₃ OD)?: 8.23 (1H, s), 7.67 (1H, s), 7.37-7.30 (2H, m), 7.18-7.13 = 7.1 Hz), 4.85-4.82 (1H, m), 4.33-4.31 (1H, m), 4.27-4.25 (1H, m), 3.43-3.34 (2H, m). LCMS (ESI) m / z 497 [M + H].

Reference Example 74

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-phenyl] -1,1-dioxo-1,4-

(Step 1) Synthesis of 4- (4-ethynyl-3,5-difluorophenyl) thiomorpholine-1,1-dioxide

Following the procedure of Reference Example 70, Step 3, 4- (4-ethynyl-3,5-difluoro-benzoyl) Phenyl) thiomorpholine, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 6.40 (2H, d, J = 10.2 Hz), 3.92-3.88 (4H, m), 3.42 (1H, s), 3.11-3.06 (4H, m). LCMS (ESI) m / z 272 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 74

(4-ethynyl-3,5-difluorophenyl) thiomorpholine-1,1-dioxane was used instead of 2-ethynyl-1,3-difluorobenzene in accordance with Referential Example 1, Using the seed, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.90 (1H, s), 7.36-7.32 (1H, m), 6.95 (2H, d, J = 11.4㎐), 6.60 (2H , 5.92 (1H, d, J = 7.0 Hz), 5.39 (1H, d, J = 6.2 Hz), 5.24-5.22 (1H, m), 4.60-4.55 1H, m), 4.06-4.03 (1H, m), 3.95-3.89 (4H, m), 3.25-3.17 (1H, m), 3.17-3.09 (5H, m). LCMS (ESI) m / z 614 [M + H] &lt; ⁺ &gt;.

Reference Example 75

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 6-fluoro-4 - [(3R) -3-fluoropyrrolidin-1-yl] phenyl] ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 2,6-difluoro-4 - [(3R) -fluoropyrrolidin-1-yl] benzaldehyde

According to Reference Example 23, Step 1, 2-ethynyl-1,3,5-trifluorobenzene and 2,4,6-trifluorobenzaldehyde instead of morpholine, (R) -3-fluoropyrrole Pyridine, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 10.07 (1H, s), 6.04 (2H, d, J = 12.5㎐), 5.47-5.32 (1H, m), 3.64-3.51 (4H, m), 2.50-2.41 (1 H, m), 2.28-2.08 (1 H, m). LCMS (ESI) m / z 230 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2- (ethylthio) -6-fluoro-4 - [(3R) -3-fluoropyrrolidin- 1-yl] benzaldehyde

Following the procedure of Reference Example 70, Step 2, 2,6-difluoro-4 - [(3R) -fluoropyrrolidone was used instead of 2,6-difluoro-4- (pyrrolidin- 1-yl] benzaldehyde, the titled compound was obtained.

¹ H-NMR (CDCl ₃ ) ?: 10.21 (1H, s), 6.11 (1H, d, J = 1.8 Hz), 6.01 (1H, dd, J = 13.9, 1.8 Hz), 5.47-5.33 ), 3.70-3.52 (4H, m), 2.92 (2H, q, J = 7.3 Hz), 2.49-2.40 (1H, m), 2.28-2.09 ㎐). LCMS (ESI) m / z 272 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 2- (ethylsulfonyl) -6-fluoro-4 - [(3R) -3-fluoropyrrolidin-1-yl] benzaldehyde

According to Reference Example 70, Step 3, 2- (ethylthio) -6-fluoro-4- [2-fluoro-4- (pyridin- (3R) -3-fluoropyrrolidin-1-yl] benzaldehyde, the titled compound was obtained.

¹ H-NMR (CDCl ₃ )?: 10.31 (1H, s), 7.21 (1H, d, J = 2.3 Hz), 6.38 (1H, dd, J = 13.7, 2.3 Hz), 5.51-5.35 ), 3.74-3.60 (6H, m), 2.53-2.45 (1H, m), 2.29-2.14 (1H, m), 1.32 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 304 [M + H] &lt; ^{+ &}

(Step 4) Synthesis of (3R) -1- (3-ethylsulfonyl-4-ethynyl-5-fluoro-phenyl) -3-fluoro-pyrrolidine

(Ethylsulfonyl) -6-fluoro-4 - [(3R) -3-fluoropyrrolidin-l-ylmethyl) -One] benzaldehyde, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.03 (1H, d, J = 2.4㎐), 6.42 (1H, dd, J = 11.7, 2.4㎐), 5.47-5.33 (1H, m), 3.66-3.64 (2H m), 3.61-3.46 (5H, m), 2.49-2.40 (1H, m), 2.29-2.11 (1H, m), 1.27 (3H, t, J = 7.5 Hz). LCMS (ESI) m / z 300 [M + H] &lt; ^{+ &}

(Step 5) Reference Example Synthesis of Compound 75

(3R) -1- (3-Ethylsulfonyl-4-ethynyl-5-fluoro-phenyl) - By using 3-fluoro-pyrrolidine, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.20 (1H, s), 7.60 (1H, s), 6.99 (1H, d, J = 2.6㎐), 6.66 (1H, dd, J = 12, 2.6㎐) , 5.86 (1H, d, J = 7.0 Hz), 5.47-5.34 (1H, m), 4.81-4.78 (1H, m), 4.31-4.29 M), 3.41-3.32 (2H, m), 2.42-2.15 (2H, m), 1.24 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 642 [M + H].

Reference Example 76

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [ Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 5- (benzyloxy) -2-bromopyrimidine

(200 mg, 1.1 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and N, N-dimethylformamide (1 mL), and potassium carbonate (170 mg, 1.3 mmol) and benzyl bromide (0.15 mL, 1.3 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate and water were added to the reaction solution to separate layers, and the organic layer was washed with water and saturated brine. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give 5- (benzyloxy) -2-bromopyrimidine (200 mg, 0.75 mmol , 66%) as a white powder.

¹ H-NMR (CDCl ₃ )?: 8.31 (2H, s), 7.45-7.36 (5H, m), 5.15 (2H, s). LCMS (ESI) m / z 265 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine

(200 mg, 0.75 mmol), ethynyltriisopropylsilane (0.34 mL, 1.5 mmol), bis (triphenylphosphine) palladium (II) dichloride (53 mg, (14 mg, 0.075 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol) were suspended in tetrahydrofuran (2 mL). The reaction solution was stirred at 70 DEG C for 1 hour and 30 minutes, filtered through celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine (120 mg, 0.32 mmol, 43 %) As a yellow oily substance.

¹ H-NMR (CDCl ₃ )?: 8.42 (2H, s), 7.43-7.36 (5H, m), 5.18 (2H, s), 1.17-1.13 (21H, m). LCMS (ESI) m / z 367 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 5- (benzyloxy) -2-ethynylpyrimidine

(120 mg, 0.32 mmol) was dissolved in tetrahydrofuran (1 mL), and a solution of tetrabutylammonium fluoride (1M tetrabutylammonium fluoride solution Hydrofuran solution, 0.38 mL, 0.38 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give 5- (benzyloxy) -2- ethynylpyrimidine (45 mg, 0.21 mmol, 67% As a yellow powder.

¹ H-NMR (CDCl ₃ )?: 8.43 (2H, s), 7.44-7.38 (5H, m), 5.19 (2H, s), 3.04 (1H, s). LCMS (ESI) m / z 211 [M + H] &lt; ^{+ &}

(Step 4) Reference Example Synthesis of Compound 76

According to Reference Example 1, Step 4, 5- (benzyloxy) -2-ethynylpyrimidine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.57 (2H, s), 8.26 (1H, s), 7.75 (1H, s), 7.49-7.33 (5H, m), 5.87 (1H, d, J = 6.8 Hz), 5.30 (2H, s), 4.84-4.79 (1H, m), 4.32-4.27 (1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 553 [M + H] &lt; ⁺ &gt;.

Reference Example 77

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [ (Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of ((4- (benzyloxy) -2-fluorophenyl) ethynyl) trimethylsilane

(Benzyloxy) -2-fluoro-1-iodobenzene was used instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane in the same manner as in Reference Example 76, By using thionyltrimethylsilane, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.43-7.33 (6H, m), 6.77 (1H, dd, J = 10.4, 2.8 Hz), 6.70-6.67 (9H, s).

(Step 2) Synthesis of 4- (benzyloxy) -1-ethynyl-2-fluorobenzene

(4- (benzyloxy) -2-fluorophenyl) ethynyl) pyrimidine was obtained in the same manner as in Reference Example 76, Step 3, instead of 5- (benzyloxy) -2- ) Trimethylsilane, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.43-7.29 (6H, m), 6.66-6.79 (2H, m), 5.04 (2H, s), 3.25 (1H, s).

(Step 3) Reference Example Synthesis of Compound 77

According to Reference Example 1, Step 4, 4- (benzyloxy) -1-ethynyl-2-fluorobenzene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

¹ H-NMR (CD ₃ OD)?: 8.22 (1H, s), 7.56 (1H, s), 7.40-7.26 (6H, m), 6.87-6.84 = 6.8 Hz), 5.12 (2H, s), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 569 [M + H] &lt; ⁺ &gt;.

Reference Example 78

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino ) Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of N-benzyl-4 - ((triisopropylsilyl) ethynyl) aniline

Benzyl-4-iodoaniline and ethynyltriisopropylsilane were used instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane in accordance with Reference Example 76, Step 2 , The title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.37-7.25 (7H, m), 6.53 (2H, d, J = 8.8 Hz,), 4.34 (2H, s), 1.12-1.05 (21H, m). LCMS (ESI) m / z 364 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of N-benzyl-4-ethynyl aniline

Benzyl-4 - ((triisopropylsilyl) ethynyl) aniline was used instead of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine in accordance with Referential Example 76, , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.39-7.25 (7H, m), 6.55 (2H, d, J = 8.0㎐), 4.35 (2H, s), 4.28-4.19 (1H, brs), 2.96 (1H , s). LCMS (ESI) m / z 208 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 78

According to Reference Example 1, Step 4, N-benzyl-4-ethynyl aniline was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 7.60 (1H, s), 7.36-7.20 (7H, m), 6.60 (2H, d, J = 8.8㎐), 5.93 (1H, (1H, m), 3.40-3.35 (2H, m), 4.31-4.29 (2H, m) . LCMS (ESI) m / z 550 [M + H] &lt; ⁺ &gt;.

Reference Example 79

2 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] -3-fluorobenzamide

(Step 1) Synthesis of 3-fluoro-2 - ((trimethylsilyl) ethynyl) benzamide

By using 3-fluoro-2-iodobenzamide and ethynyltrimethylsilane instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane in accordance with Referential Example 76, Step 2 , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.96 (1H, d, J = 7.8㎐), 7.83-7.55 (1H, brs), 7.45-7.40 (1H, m), 7.28-7.22 (1H, m), 6.19 -5.72 (1H, br s), 0.31 (9H, s). LCMS (ESI) m / z 236 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethynyl-3-fluorobenzamide

((Trimethylsilyl) ethynyl) benzamide was used instead of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine in accordance with Referential Example 76, , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.89-7.86 (1H, m), 7.46 (1H, dt, J = 5.4, 8.0㎐), 7.30-7.21 (2H, m), 6.29-5.45 (1H, brs) , 3.77 (1 H, s). LCMS (ESI) m / z 164 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 79

According to Reference Example 1, Step 4, the title compound was obtained by using 2-ethynyl-3-fluorobenzamide instead of 2-ethynyl-1,3-difluorobenzene.

¹ H-NMR (CD ₃ OD)?: 8.23 (1H, s), 7.66 (1H, s), 7.47-7.41 (2H, m), 7.35-7.30 = 6.8 Hz), 4.82-4.75 (1H, m), 4.32-4.29 (1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 506 [M + H] &lt; ⁺ &gt;.

Reference Example 80

Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-di &lt; RTI ID = Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3,5-difluoro-2-methoxypyridine

After dissolving 2,3,5-trifluoro-4-iodopyridine (500 mg, 1.93 mmol) in methanol (3 mL), sodium methoxide (5M methanol solution, 1.15 mL) was added at room temperature, Lt; / RTI &gt; The reaction solution was partitioned between ethyl acetate and water, and the organic layer was separated, washed with water and saturated brine in this order. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain the title compound (376 mg), which was reacted with 4-ethynyl-3,5-difluoro-2-methoxypyridine And 4-ethynyl-3-fluoro-2,5-dimethoxypyridine as a mixed oil.

Using the obtained mixture, synthesis was conducted in accordance with Referential Example 76, Step 2 and Step 3, followed by separation and purification by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.87 (1H, s), 4.02 (3H, s), 3.73 (1H, s).

(Step 2) Reference Example Synthesis of Compound 80

According to Reference Example 1, Step 4, 4-ethynyl-3,5-difluoro-2-methoxypyridine was used instead of 2-ethynyl-1,3-difluorobenzene to obtain the title compound .

^{1 H-NMR (DMSO-D} 6) δ: 8.20 (1H, s), 8.19 (1H, s), 8.14 (1H, s), 7.32-7.29 (1H, m), 6.59 (2H, s), 5.94 (1H, d, J = 6.6 Hz), 5.41 (1H, d, J = 6.6 Hz), 5.24 , 4.11-4.04 (2H, m), 3.96 (3H, s). LCMS (ESI) m / z 512 [M + H] &lt; ⁺ &gt;.

Reference Example 81

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 3-fluoro-2,5-dimethoxy-4-pyridyl) ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 4-ethynyl-3-fluoro-2,5-dimethoxypyridine

From Reference Example 80, Step 1, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.76 (1H, s), 4.01 (3H, s), 3.97 (3H, s), 3.66 (1H, s).

(Step 2) Reference Example Synthesis of Compound 81

According to Reference Example 1, Step 4, 4-ethynyl-3-fluoro-2,5-dimethoxypyridine was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.26 (1H, s), 7.83 (1H, s), 7.75 (1H, s), 5.89 (1H, d, J = 6.6㎐), 4.85-4.82 (3H, (1H, m), 4.34-4.32 (1H, m), 4.29-4.26 (1H, m), 4.04 (3H, s), 3.99 m), 3.42 (1H, dd, J = 12.5, 4.4 Hz), 3.37 (1H, dd, J = 12.5, 3.7 Hz). LCMS (ESI) m / z 524 [M + H] &lt; ⁺ &gt;.

Reference Example 82

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Ethylsulfanylphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1-ethylsulfanyl-2-ethynyl-benzene

The title compound was obtained according to Referential Example 76, Step 2 and Step 3 by using 1-bromo-2-ethylsulfanyl-benzene instead of 5- (benzyloxy) -2-bromopyrimidine.

¹ H-NMR (CDCl ₃ )?: 7.49 (1H, dd, J = 7.5, 1.3 Hz), 7.33-7.25 (2H, m), 7.12 , s), 3.01 (2H, q, J = 7.5 Hz), 1.37 (3H, dd, J = 9.5, 5.1 Hz).

(Step 2) Reference Example Synthesis of Compound 82

Ethyl sulfanyl-2-ethynyl-benzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4 to obtain the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 7.91 (1H, s), 7.52 (1H, dd, J = 7.7, 1.1㎐), 7.44-7.36 (3H, m), 7.23 (1H, d, J = 1.5, 7.3 Hz), 6.61 (2H, s), 5.93 (1H, d, J = 7.0 Hz), 5.41 (2H, m), 3.23-3.19 (1H, m), 3.13 (1H, dd, J = 8.1, 5.1 Hz), 4.59 3.05 (2H, q, J = 7.5 Hz), 1.29 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 505.3 [M + H] &lt; ⁺ &gt;.

Reference Example 83

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl) ethynyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of triisopropyl (thiochroman-8-ylethynyl) silane

According to Reference Example 76, Step 2, 8-iodothiochroman was used instead of 5- (benzyloxy) -2-bromopyrimidine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.27-7.25 (1H, m), 6.97-6.93 (1H, m), 6.89 (1H, t, J = 7.6㎐), 3.07-3.04 (2H, m), 2.80 (2H, t, J = 6.1 Hz), 2.12-2.06 (2H, m), 1.26-1.04 (21 H, m).

(Step 2) Synthesis of 8-ethynylthiocromene

(Thiochroman-8-ylethynyl) silane was used instead of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine in accordance with Referential Example 76, Step 3 , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.31-7.26 (1H, m), 7.02-6.98 (1H, m), 6.92 (1H, t, J = 7.6㎐), 3.45 (1H, s), 3.09-3.06 (2H, m), 2.82 (2H, t, J = 6.1 Hz), 2.13-2.07 (2H, m).

(Step 3) Synthesis of 8-ethynylthiocroman 1,1-dioxide

Dioxane (1 mL) and water (0.50 mL) were added to 8-ethynylthiochroman (59 mg, 0.34 mmol), oxone (420 mg, 0.68 mmol) was added under ice- And stirred overnight. Ethyl acetate, a saturated aqueous sodium hydrogencarbonate solution and water were added to the reaction solution at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (51 mg, 0.25 mmol, 73%) as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ: 7.55 (1H, d, J = 7.8㎐), 7.38 (1H, t, J = 7.8㎐), 7.21 (1H, dd, J = 7.8, 1.0㎐), 3.59 ( 1H, s), 3.44-3.41 (2H, m), 3.01 (2H, t, J = 6.2Hz), 2.48-2.42 (2H, m). LCMS (ESI) m / z 207 [M + H] &lt; ^{+ &}

(Step 4) Reference Example Synthesis of Compound 83

According to Reference Example 1, Step 4, the title compound was obtained by using 8-ethynylthiocromethane 1,1-dioxide instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.22 (1H, s), 7.69 (1H, s), 7.57 (1H, d, J = 7.6㎐), 7.48 (1H, t, J = 7.6㎐), 7.30 (1H, d, J = 7.6 Hz), 5.87 (1H, d, J = 6.8 Hz), 4.83-4.79 (1H, m), 4.32-4.30 3.54-3.51 (2H, m), 3.43-3.33 (2H, m), 3.07 (2H, t, J = 6.0Hz), 2.43-2.38 (2H, m). LCMS (ESI) m / z 549 [M + H].

Reference Example 84

2 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] -3-fluoro-benzenesulfonamide

(Step 1) Synthesis of 3-fluoro-2 - ((trimethylsilyl) ethynyl) benzenesulfonamide

According to Reference Example 76, Step 2, 3-fluoro-2-iodobenzenesulfonamide and ethynyltrimethylsilane were used instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane To obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 7.85 (1H, d, J = 7.8 Hz), 7.45-7.41 (1H, m), 7.31-7.27 , s). LCMS (ESI) m / z 272 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethynyl-3-fluorobenzenesulfonamide

Fluoro-2 - ((trimethylsilyl) ethynyl) benzenesulfonamide instead of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine was obtained in accordance with Referential Example 76, , The title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.88 (1H, d, J = 7.8 Hz), 7.52-7.47 (1H, m), 7.37-7.31 , s). LCMS (ESI) m / z 200 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 84

According to Reference Example 1, Step 4, the title compound was obtained by using 2-ethynyl-3-fluorobenzenesulfonamide instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.30 (1H, s), 7.85 (1H, d, J = 7.8㎐), 7.74 (1H, s), 7.54-7.49 (1H, m), 7.46-7.41 ( (1H, m), 5.88 (1H, d, J = 6.8 Hz), 4.84-4.81 (1H, m), 4.33-4.30 m). LCMS (ESI) m / z 542 [M + H].

Reference Example 85

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- [ (Sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 3-fluoro-2 - ((trimethylsilyl) ethynyl) benzonitrile

By using 3-fluoro-2-iodobenzonitrile and ethynyltrimethylsilane instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane in accordance with Referential Example 76, Step 2 , The title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.46-7.44 (1H, m), 7.41-7.35 (1H, m), 7.33-7.29 (1H, m), 0.31 (9H, s). LCMS (ESI) m / z 218 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2-ethynyl-3-fluorobenzonitrile

((Trimethylsilyl) ethynyl) benzonitrile was used instead of 5- (benzyloxy) -2 - ((triisopropylsilyl) ethynyl) pyrimidine according to Referential Example 76, Step 3 , The title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.51 (1H, dd, J = 7.7, 1.5 Hz), 7.49-7.44 (1H, m), 7.39-7.35 (1H, m), 3.72 (1H, s).

(Step 3) Reference Example Synthesis of Compound 85

According to Reference Example 1, Step 4, 2-ethynyl-3-fluorobenzonitrile was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.27 (1H, s), 7.79 (1H, s), 7.66-7.64 (1H, m), 7.57-7.53 (2H, m), 5.88 (1H, d, J = 6.8 Hz), 4.84-4.80 (1H, m), 4.33-4.31 (1H, m), 4.28-4.26 (1H, m), 3.45-3.35 (2H, m). LCMS (ESI) m / z 488 [M + H].

Reference Example 86

Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-6-fluoro-phenyl] -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of 1- (cyclopropylmethoxy) -3-fluoro-2-iodobenzene

(200 mg, 0.84 mmol) was dissolved in tetrahydrofuran (2 mL), and cyclopropylmethanol (0.14 mL, 1.7 mmol), triphenylphosphine (440 mg, 1.7 mmol), diisopropyl azodicarboxylate (0.33 ml, 1.7 mmol) was added in an ice bath, and the mixture was stirred for 2 hours in an ice bath. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 1- (cyclopropylmethoxy) -3-fluoro-2-iodobenzene (192 mg) As a yellow oily substance.

¹ H-NMR (CDCl ₃ )?: 7.26-7.19 (1H, m), 6.72-6.67 (1H, m), 6.57 (1H, d, J = 8.3 Hz) ), 1.33-1.28 (1H, m), 0.68-0.63 (2H, m), 0.44-0.41 (2H, m).

(Step 2) Synthesis of ((2- (cyclopropylmethoxy) -6-fluorophenyl) ethynyl) trimethylsilane

(Cyclopropylmethoxy) -3-fluoro-2-iodobenzene was used instead of 5- (benzyloxy) -2-bromopyrimidine and ethynyltriisopropylsilane in the same manner as in Reference Example 76, , Ethynyltrimethylsilane was used to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.17 (1H, dt, J = 6.6, 8.4㎐), 6.69-6.64 (1H, m), 6.61 (1H, d, J = 8.5㎐), 3.91 (2H, d , J = 6.3 Hz), 1.31-1.24 (1H, m), 0.64-0.60 (2H, m), 0.45-0.41 (2H, m), 0.28 (9H, s).

(Step 3) Synthesis of 1- (cyclopropylmethoxy) -2-ethynyl-3-fluorobenzene

((2- (cyclopropylmethoxy) -6-fluorophenyl) -6-fluoropyridine instead of 5- (benzyloxy) -2 - Yl) trimethylsilane, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.24 (1H, dt, J = 6.6, 8.4㎐), 6.72 (1H, t, J = 8.4㎐), 6.67 (1H, J = 8.4㎐), 3.93 (2H, d, J = 6.6 Hz), 3.52 (1H, s), 1.36-1.30 (1H, m), 0.68-0.63 (2H, m), 0.43-0.39 (2H, m).

(Step 4) Reference Example Synthesis of Compound 86

(Cyclopropylmethoxy) -2-ethynyl-3-fluorobenzene was used instead of 2-ethynyl-1,3-difluorobenzene according to Referential Example 1, Step 4, the title compound was obtained .

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.25 (1H, s), 7.59 (1H, s), 7.33-7.27 (1H, m), 6.88 (1H, d, J = 8.5㎐), 6.79 (1H, (1H, m, J = 8.5 Hz), 5.88 (1H, d, J = 7.0 Hz), 4.86-4.83 (1H, m), 4.34-4.32 (d, J = 7.0 Hz), 3.44-3.34 (2H, m), 1.40-1.32 (1H, m), 0.73-0.68 (2H, m), 0.43 (2H, m). LCMS (ESI) m / z 533 [M + H].

Reference Example 87

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 4- (3-pyridylmethoxy) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

Pyrrolo [2,3-d] pyrimidin-2-yl] -methanone (Step 1) Pyrimidin-7-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- (500 mg, 0.82 mmol), ethynyltrimethylsilane (240 mg, 2.5 mmol) was added to a solution of 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol- ), Bis (triphenylphosphine) palladium (II) dichloride (58 mg, 0.082 mmol), copper iodide (16 mg, 0.082 mmol) and diisopropylethylamine (0.28 mL, 1.6 mmol) were dissolved in tetrahydrofuran 5 mL). The reaction solution was stirred at 70 ° C overnight, filtered through celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (339 mg, 0.58 mmol, 71%) as yellow amorphous.

_{^{1 H-NMR (CDCl 3)}} δ: 9.41 (1H, brs), 8.50 (1H, s), 7.16 (1H, s), 5.98 (2H, brs), 5.63 (1H, d, J = 4.6㎐), (2H, m), 1.59 (3H, s), 1.43 (9H, s), 5.25-5.21 (1H, m), 5.07-5.03 1.34 (3H, s), 0.26 (9H, s). LCMS (ESI) m / z 581 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of tert-butyl N - ((3aR, 4R, 6R, 6aR) -6- (4-Amino-5-ethynyl-7H-pyrrolo [2,3- d] pyrimidin- ) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate

7H-pyrrolo [2,3-d] pyrimidin-7-one obtained in the step (1) Yl) methyl) sulfamoylcarbamate (339 mg, 0.58 mmol) was dissolved in tetrahydrofuran (2 ml) 6.8 mL), and a tetrabutylammonium fluoride solution (1M tetrahydrofuran solution, 0.70 mL, 0.70 mmol) was added at room temperature, followed by stirring at room temperature for 25 minutes. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (260 mg, 0.51 mmol, 88%) as a yellow powder.

_{^{1 H-NMR (CDCl 3)}} δ: 9.25 (1H, brs), 8.51 (1H, s), 7.20 (1H, s), 6.11 (2H, brs), 5.65 (1H, d, J = 4.6㎐), (2H, m), 3.25 (1H, s), 1.61 (3H, s), 1.44 (9H, s), 1.35 (3H, s). LCMS (ESI) m / z 509 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 87

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- (2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate (20 mg, 0.039 mmol) (1 mg, 0.0053 mmol) and diisopropylethylamine (0.013 mmol) were added to a solution of 2-amino-2- mL, 0.079 mmol) was suspended in tetrahydrofuran (0.30 mL). The reaction solution was stirred at 70 ° C overnight, a mixed solution (0.60 mL) of trifluoroacetic acid / water = 4/1 was added at room temperature, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (2.1 mg, 0.0039 mmol, 10%) as yellow powder.

¹ H-NMR (CD ₃ OD)?: 8.65-8.60 (1H, m), 8.55-8.50 (1H, m), 8.24 (1H, s), 7.95-7.90 m), 7.05-7.00 (2H, br s), 5.84-5.82 (1H, br s), 5.19 (2H, s), 4.80-4.70 (2H, m). LCMS (ESI) m / z 552 [M + H] &lt; ⁺ &gt;.

Reference Example 88

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 3-fluoro-2-pyridyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 87, Step 3, 3-fluoro-2-iodopyridine was used instead of 3 - ((4-iodophenoxy) methyl) pyridine to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.43-8.39 (1H, m), 8.26 (1H, s), 7.78 (1H, s), 7.78-7.71 (1H, m), 7.50-7.46 (1H, m ), 5.88 (1H, d, J = 7.1 Hz), 4.90-4.60 (1H, m), 4.33-4.31 (1H, m), 4.28-4.25 (1H, m), 3.40-3.31 (2H, m). LCMS (ESI) m / z 464 [M + H] &lt; ⁺ &gt;.

Reference Example 89

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-methylsulfanylphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(2-iodophenyl) (methyl) sulfane was used instead of 3 - ((4-iodophenoxy) methyl) pyridine according to Referential Example 87, Step 3 to obtain the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.24 (1H, s), 7.62 (1H, s), 7.48-7.46 (1H, m), 7.37-7.34 (2H, m), 7.22-7.16 (1H, m ), 5.86 (1H, d, J = 8.0 Hz), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 2.55 (3 H, s). LCMS (ESI) m / z 491 [M + H] &lt; ⁺ &gt;.

Reference Example 90

2 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] benzenesulfonamide

According to Reference Example 87, Step 3, the title compound was obtained by using 2-iodobenzenesulfonamide in place of 3 - ((4-iodophenoxy) methyl) pyridine.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 8.02 (1H, dd, J = 8.0, 4.0㎐), 7.74 (1H, dd, J = 7.8, 4.0㎐), 7.71 (1H, (1H, m), 7.85-7.56 (1H, m), 7.53-7.49 (1H, m), 5.87 (1H, d, J = 6.8Hz), 4.83-4.81 , 4.27-4.25 (IH, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 524 [M + H] &lt; ⁺ &gt;.

Reference Example 91

3 - [[4- [2- [4-Amino-7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] phenoxy] methyl] benzamide

According to Reference Example 87, Step 3, the title compound was obtained by using 3 - ((4-iodophenoxy) methyl) benzamide instead of 3 - ((4-iodophenoxy) methyl) pyridine.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J = 8.1㎐), 7.65 (1H, d, J = 8.0㎐), 7.54 (1H, s), 7.54-7.49 (1H, m), 7.48 (2H, d, J = 8.0 Hz), 7.05 , 5.19 (2H, s), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m / z 594 [M + H] &lt; ⁺ &gt;.

Reference Example 92

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2,3-d] pyrimidin-5-yl] ethynyl] isoquinoline

According to Reference Example 87, Step 3, 4-iodoisoquinoline was used instead of 3 - ((4-iodophenoxy) methyl) pyridine to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 9.20 (1H, s), 8.69 (1H, s), 8.34 (1H, d, J = 8.3㎐), 8.26 (1H, s), 8.16 (1H, d, J = 8.3 Hz), 7.95-7.90 (1H, m), 7.81 (1H, s), 7.80-7.74 (1H, m), 5.92 ), 4.36-4.33 (IH, m), 4.29-4.25 (IH, m), 3.43-3.39 (2H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 93

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- (1-naphthyl) Ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) ((3aR, 4R, 6R, 6aS) -6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta [d] [1,3] dioxol- , 6R, 7S, 7aR) -6-amino-2,2-dimethylhexahydrocyclopenta [d] [1,3] dioxin-

(Hydroxymethyl) cyclopentane-1,2-diol hydrochloride (40 g, 218 mmol) was dissolved in methanol (400 mL) and 2,2-dimethoxypropane (54 mL, 436 mmol), mesic acid (14 mL, 218 mmol) was added dropwise with stirring at an inner temperature of 7 ° C or lower while stirring with an ice bath. After stirring in an ice bath for 5 minutes and at room temperature overnight, triethylamine (122 mL, 872 mmol) was added dropwise in an ice bath to maintain the internal temperature at 10 캜 or lower. After stirring under an ice bath for 5 minutes and at room temperature for 30 minutes, the solvent was distilled off under reduced pressure to obtain the title compound as a crude admixture (102 g).

LCMS (ESI) m / z 188 [M + H] &lt; ^{+ &}

(Step 2) ((3aR, 4R, 6R, 6aS) -6- (4-Chloro-7H- pyrrolo [2,3- d] pyrimidin- 7-yl) -2,2-dimethyltetrahydro- (4aR, 6R, 7S, 7aR) -6- (4-Chloro-7H-pyrrolo [2,3- d] pyrimidine -7-yl) -2,2-dimethylhexahydrocyclopenta [d] [1,3] dioxin-7-ol

(3aR, 4R, 6R, 6aS) -6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol- ) Mixture of methanol and (4aR, 6R, 7S, 7aR) -6-amino-2,2-dimethylhexahydrocyclopenta [d] [1,3] dioxin- (46 mL, 240 mmol) was suspended in 2-butanol (400 mL), triethylamine (61 mL, 436 mmol) was added at room temperature, and the reaction solution was stirred overnight at 80 ° C Lt; / RTI &gt; After the reaction solvent was distilled off under reduced pressure, ethyl acetate and an aqueous solution of sodium hydrogencarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off to obtain the title compound as a crude isomer mixture (72 g).

LCMS (ESI) m / z 324 [M + H] &lt; ^{+ &}

(3R, 4R, 6R, 6aS) -6- (4-chloro-7H-pyrrolo [2,3- d] pyrimidin- - cyclopenta [d] [1,3] dioxol-4-yl) methanol

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- Cyclopenta [d] [1,3] dioxol-4-yl) methanol and (4aR, 6R, 7S, 7aR) -6- (4-chloro-7H- pyrrolo [2,3 d] [1,3] dioxin-7-ol (72 g) was suspended in acetone (720 ml) Under an ice bath, mesyl acid (14.2 mL, 218 mmol) was added. The reaction solution was stirred under an ice bath for 40 minutes at room temperature overnight, and then triethylamine (122 mL, 872 mmol) was added dropwise to an internal temperature of 10 ° C or less in an ice bath. After stirring for 10 minutes in an ice bath and 30 minutes at room temperature, the solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain the crude title compound (77 g) as a brown oily substance.

_{^{1 H-NMR (CDCl 3)}} δ: 8.63 (1H, s), 7.33 (1H, d, J = 3.7㎐), 6.63 (1H, d, J = 3.7㎐), 5.03-4.95 (2H, m), (2H, m), 2.38-2.32 (1H, m), 2.18-2.16 (1H, m), 3.90-3.86 , &lt; / RTI &gt; m), 1.60 (3H, s), 1.32 (3H, s). LCMS (ESI) m / z 324 [M + H] &lt; ^{+ &}

(Step 4) 7 - ((3aS, 4R, 6R, 6aR) -6 - (((tert- Butyldimethylsilyl) oxy) methyl) -2,2- dimethyltetrahydro-3aH-cyclopenta [ , 3] dioxol-4-yl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2 (4H) -quinolinone obtained in Reference Example 93, Step 3 (77 g) was dissolved in N, N-dimethylformamide (770 ml), and then imidazole (37 g, Butyldimethylchlorosilane (58 g, 382 mmol) was added in a water bath (25 ° C), followed by stirring in a water bath (29 ° C) for 40 minutes. Ethyl acetate (800 mL) and water (800 mL) were added to the reaction solution under an ice bath, and the organic layer was washed with water (400 mL). After removing the water layer of about 300 mL, it was washed with saturated brine (100 mL), and further washed with saturated brine (400 mL). After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain 79 g of the title compound (83% in the fourth step) as yellow oily substance.

_{^{1 H-NMR (CDCl 3)}} δ: 8.62 (1H, s), 7.31 (1H, d, J = 3.7㎐), 6.63 (1H, d, J = 3.7㎐), 5.09-5.04 (1H, m), (3H, m), 1.59 (3H, s), 1.31 (3H, m), 4.88 (1H, s), 0.93 (9H, s), 0.087 (3H, s), 0.074 (3H, s). LCMS (ESI) m / z 438 [M + H] &lt; ^{+ &}

(Step 5) 7 - ((3aS, 4R, 6R, 6aR) -6 - (((tert- Butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-3aH-cyclopenta [ , 3] dioxol-4-yl) -4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine

Cyclopenta [d] [1, 3] di (tert-butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] Yl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine (79 g, 180 mmol) was dissolved in N, N-dimethylformamide (790 mL) Succinic acid imide (45 g, 198 mmol) was added and the mixture was stirred at 50 占 폚 for 11 hours and at room temperature for 12 hours. Ethyl acetate (600 mL), saturated sodium hydrogen sulfite (300 mL) and water (600 mL) were added to the reaction solution in an ice bath, and the mixture was stirred at room temperature for 10 minutes. After the layer was separated, the organic layer was washed successively with a mixture of water (600 mL) and saturated brine (100 mL) and saturated brine (500 mL). After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the crude title compound (95 g) as a brown oily substance.

_{^{1 H-NMR (CDCl 3)}} δ: 8.61 (1H, s), 7.46 (1H, s), 5.08-5.04 (1H, m), 4.85 (1H, t, J = 6.3㎐), 4.64-4.62 (1H (3H, s), 1.30 (3H, s), 0.94 (9H, s), 0.095 (3H, s), 3.81-3.73 (2H, m), 2.42-2.32 0.082 (3H, s). LCMS (ESI) m / z 564 [M + H] &lt; ^{+ &}

(6R, 4R, 6R, 6aS) -6- (4-Chloro-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- Synthesis of dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol

The crude 7 - ((3aS, 4R, 6R, 6aR) -6 - (((tert- butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-3aH-cyclo Pyrido [2,3-d] pyrimidine (95 g) was dissolved in tetrahydrofuran (950 ml), and the mixture was stirred at room temperature for 3 hours. After dissolution, a tetrabutylammonium fluoride solution (1M tetrahydrofuran solution, 180 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Under an ice bath, ethyl acetate (500 mL), water (500 mL) and saturated aqueous sodium bicarbonate (300 mL) were added and the layers were separated, and the aqueous layer was extracted with ethyl acetate (500 mL). The organic layer was washed with saturated brine (500 mL), dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (70 g, 86% in two steps) as pale green amorphous.

_{^{1 H-NMR (CDCl 3)}} δ: 8.62 (1H, s), 7.48 (1H, s), 5.05-4.99 (1H, m), 4.91 (1H, t, J = 6.5㎐), 4.71-4.68 (1H (1H, m), 3.89-3.85 (1H, m), 3.82-3.78 (1H, m), 2.50-2.45 (2H, m), 2.31-2.27 (3 H, s), 1.31 (3 H, s). LCMS (ESI) m / z 450 [M + H] &lt; ^{+ &}

(Step 7) ((3aR, 4R, 6R, 6aS) -6- (4-Amino-5-iodo-7H- pyrrolo [2,3- d] pyrimidin- Synthesis of dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyltetrahydro-benzo [b] thiophene- Cyclopenta [d] [1,3] dioxol-4-yl) methanol (70 g) was dissolved in 1,4-dioxane (350 mL), 28% ammonia water (350 mL) was added at room temperature, Lt; 0 &gt; C overnight. The solvent was distilled off under reduced pressure, suspended in water (700 mL), and stirred overnight at room temperature. The precipitate was filtered out, washed with water (420 mL) and dried to give the title compound (67 g, 99%) as a pale brown powder.

_{^{1 H-NMR (CDCl 3)}} δ: 8.26 (1H, s), 7.12 (1H, s), 5.69-5.67 (2H, brs), 4.94 (1H, t, J = 6.2㎐), 4.90-4.84 (1H m), 4.72-4.70 (1H, m), 3.89-3.85 (1H, m), 3.81-3.77 (1H, m), 3.06-3.04 -2.27 (1H, m), 1.59 (3H, s), 1.33 (3H, s) LCMS (ESI) m / z 431 [M + H] ⁺ .

(Step 8) 7 - ((3aS, 4R, 6R, 6aR) -6- (Aminomethyl) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol- ) -5-iodo-7H-pyrrolo [2,3-d] pyrimidin-4-amine

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyltetrahydro-benzo [b] thiophene- (51 g, 118 mmol) and phthalimide (35 g, 236 mmol) were dissolved in tetrahydrofuran (1000 mL), and then triphenylphosphine Phosphine (93 g, 354 mmol) was added. After dissolving triphenylphosphine, diisopropyl azodicarboxylate (70 mL, 354 mmol) was added dropwise under ice-cooling with stirring. The reaction solution was stirred for 30 minutes under ice-cooling, then stirred at room temperature for 90 minutes, and the reaction solution was distilled off under reduced pressure. Ethanol (750 mL), hydrazine monohydrate (25 mL, 519 mmol) and water (150 mL) were added to the residue, and the mixture was stirred overnight at 80 ° C. The solvent was distilled off under reduced pressure, and then chloroform, water and a saturated aqueous solution of sodium hydrogen carbonate were added thereto to separate layers. The aqueous layer was separated and extracted with chloroform. The organic layer was combined, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (52g, 89wt%) as yellow amorphous.

_{^{1 H-NMR (CDCl 3)}} δ: 8.27 (1H, s), 7.13 (1H, s), 5.62-5.60 (2H, brs), 4.96-4.90 (2H, m), 4.56 (1H, t, J = M), 2.17-2.08 (1H, m), 1.58 (3H, s), 2.27 1.32 (3 H, s). LCMS (ESI) m / z 430 [M + H] &lt; ⁺ &gt;.

(Step 9) To a solution of tert-butyl N - ((3aR, 4R, 6R, 6aS) -6- (4-Amino-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- ) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate

Cyclopenta [d] [l, 3] di (tert-butoxycarbonyl) amide obtained in Reference Example 93, Step 8, (51.5 g, 89 wt%, ca. 107 mmol) was dissolved in acetonitrile (515 mL), and the solution was stirred at room temperature for 3 hours. Azoniabicyclo [2.2.2] octane-4-ylsulfonyl (tert-butoxycarbonyl) azanide: 1,4-diazabicyclo [2.2.2] octane monohydrochloride (Organic Letters, 2012, 10, 2626-2629) (70.5 g, 160 mmol) was added. After the reaction solution was stirred at room temperature for 30 minutes, water (1030 mL) and saturated ammonium chloride water (258 mL) were added to the reaction solution, followed by stirring at room temperature for 5 hours. The precipitate was filtered out, washed with water (1545 mL) and dried to obtain the title compound (57.1 g, 88%) as a yellowish white powder.

_{^{1 H-NMR (CDCl 3)}} δ: 8.33 (1H, s), 7.05 (1H, s), 6.62-6.60 (1H, brs), 5.73-5.71 (2H, brs), 4.99 (1H, t, J = M), 2.57-2.46 (2H, m), 2.38 (1H, m), 4.78-4.72 -2.32 (1H, m), 1.56 (3H, s), 1.48 (9H, s), 1.29 (3H, s). LCMS (ESI) m / z 609 [M + H] &lt; ⁺ &gt;.

(Step 10) Reference Example Synthesis of Compound 93

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- Cyclopenta [d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate (20 mg, 0.033 mmol), 1-ethynylnaphthalene (10 mg, 0.066 (1 mg, 0.0053 mmol) and diisopropylethylamine (0.011 mL, 0.066 mmol) were dissolved in tetrahydrofuran (3 mL) and tetrahydrofuran (0.30 mL). After the reaction solution was stirred at 70 ° C for 1 hour, a mixed solution (0.60 mL) of trifluoroacetic acid / water = 4/1 was added at room temperature, and the mixture was stirred overnight at room temperature. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (8.2 mg, 50%) as a yellow powder.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.36 (1H, d, J = 8.5㎐), 8.17 (1H, s), 7.93-7.89 (2H, m), 7.78-7.75 (1H, m), 7.74 ( (1H, s), 7.64-7.47 (3H, m), 5.02-4.95 (1H, m), 4.47-4.44 (1H, m), 4.05-4.03 2.52-2.44 (1H, m), 2.37-2.28 (1H, m), 1.90-1.82 (1H, m). LCMS (ESI) m / z 493 [M + H] &lt; ⁺ &gt;.

Reference Example 94

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- Ethoxyphenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, 2-ethynyl-1,3-dimethoxybenzene was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.12 (1H, s), 7.52 (1H, s), 7.27 (1H, t, J = 8.5㎐), 6.68 (2H, d, J = 8.5㎐), 4.95 M), 2.50-2.40 (1 H, m), 3.91 (6H, s), 3.30-3.13 , 2.34-2.28 (1 H, m), 1.85-1.73 (1 H, m). LCMS (ESI) m / z 503 [M + H] &lt; ⁺ &gt;.

Reference Example 95

Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, 2-ethynyl-1-fluoro-3-methoxybenzene was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.59 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J = 8.5㎐), 6.78-6.74 ( (1H, m), 4.97-4.86 (1H, m), 4.43-4.39 (1H, m), 4.03-4.00 3.14 (1H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.85-1.73 (1H, m). LCMS (ESI) m / z 491 [M + H] &lt; ⁺ &gt;.

Reference Example 96

Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] quinoline

According to Reference Example 93, Step 10, the title compound was obtained by using 8-ethynylquinoline instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 9.04-9.02 (1H, m), 8.40-8.35 (1H, m), 8.16 (1H, s), 7.94-7.85 (2H, m), 7.63 (1H, s ), 7.61-7.57 (2H, m), 5.00-4.91 (1H, m), 4.46-4.42 (1H, m), 4.05-4.00 (1 H, m), 2.34-2.28 (1 H, m), 1.87-1.81 (1 H, m). LCMS (ESI) m / z 494 [M + H] &lt; ⁺ &gt;.

Reference Example 97

Methyl] cyclopentyl] -5- [2- (2-ethoxy-benzyl) -2,3-dihydroxy- 6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) According to Reference Example 93, Step 10, the title compound was obtained by using 1-ethoxy-2-ethynyl-3-fluorobenzene in place of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.14 (1H, s), 7.60 (1H, s), 7.32-7.26 (1H, m), 6.86 (1H, d, J = 8.5㎐), 6.79-6.74 ( (1H, m), 5.00-4.91 (1H, m), 4.45-4.42 (1H, m), 4.23 (2H, q, J = 7.1Hz), 4.05-4.00 (1H, m), 3.21-3.15 (1H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.87-1.81 . LCMS (ESI) m / z 505 [M + H] &lt; ⁺ &gt;.

(Step 2) 4-Amino-7 - [(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- -Ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine hydrochloride

The title compound hydrochloride was obtained in accordance with Referential Example 1, Step 5.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.32 (1H, s), 7.95 (1H, s), 7.38-7.34 (1H, m), 6.93 (1H, d, J = 8.5㎐), 6.84-6.80 ( (1H, m), 5.13-5.09 (1H, m), 4.41-4.37 (1H, m), 4.27 (2H, q, J = 7.0 Hz), 4.02-4.00 (1H, m), 3.19-3.13 (1H, m), 2.47-2.42 . LCMS (ESI) m / z 505 [M + H] &lt; ^{+ &}

Reference Example 98

Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, 2-ethynyl-1-fluoro-3-methylsulfanyl-benzene was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.15 (1H, s), 7.67 (1H, s), 7.35-7.30 (1H, m), 7.10 (1H, d, J = 7.8㎐), 6.98-6.92 ( M), 5.00-4.91 (1H, m), 4.45-4.40 (1H, m), 4.05-4.00 (1H, m), 3.30-3.24 2.56 (3H, s), 2.50-2.41 (1H, m), 2.34-2.28 (1H, m), 1.87-1.78 (1H, m). LCMS (ESI) m / z 507 [M + H] &lt; ⁺ &gt;.

Reference Example 99

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- -6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, 1-ethylsulfanyl-2-ethynyl-3-fluoro-benzene was used instead of 1-ethynylnaphthalene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.15 (1H, s), 7.93 (1H, s), 7.42-7.36 (1H, m), 7.23 (1H, d, J = 8.8㎐), 7.13 (1H (t, J = 8.8 Hz), 6.65 (1H, dd, J = 6.6, 5.9 Hz), 6.53 (2H, brs), 4.90 (1H, ddd, J = 10.3, 9.9, (1H, br s), 4.24 (1H, dd, J = 8.8,5.5 Hz), 3.79 (1H, dd, J = 5.5, 3.7 Hz), 3.10-3.05 ), 2.96-2.89 (1H, m), 2.22 (1H, dt, J = 13.2, 8.1 Hz), 2.15-2.06 (1H, m), 1.61-1.53 = 7.3 Hz). LCMS (ESI) m / z 521 [M + H] &lt; ⁺ &gt;.

Reference Example 100

Methyl] cyclopentyl] -5- [2- (2-ethoxy-benzyl) -2,3-dihydroxy- 6-methoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, the title compound was obtained by using 1-ethoxy-2-ethynyl-3-methoxybenzene instead of 1-ethynylnaphthalene.

^{1 H-NMR (DMSO-D} 6) δ: 8.12 (1H, s), 7.72 (1H, s), 7.27 (1H, t, J = 8.4㎐), 6.72-6.65 (3H, m), 6.53 (2H (2H, m), 4.92-4.85 (2H, m), 4.68 (1H, d, J = 4.4 Hz), 4.25-4.20 m), 2.15-2.07 (1H, m), 1.61-1.30 (1H, m), 3.82-3.78 1.53 (1H, m), 1.37 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 517.3 [M + H] &lt; ⁺ &gt;.

Reference Example 101

4 - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2, 3-dihydroxy- 2,3-d] pyrimidin-5-yl] ethynyl] -3,5-difluoro-phenyl]

According to Reference Example 93, Step 10, 4- (4-ethynyl-3,5-difluorophenyl) morpholine was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.14 (1H, s), 7.59 (1H, s), 6.63 (2H, d, J = 11.5㎐), 4.97-4.93 (1H, m), 4.41 (1H, dd, J = 8.4,5.7 Hz), 4.01 (1H, dd, J = 5.7,3.8 Hz), 3.80 (4H, t, J = 4.9 Hz), 3.27-3.11 (6H, m), 2.48-2.40 , &lt; / RTI &gt; m), 2.35-2.25 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m / z 564 [M + H] &lt; ⁺ &gt;.

Reference Example 102

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2,3-dihydro- Dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) piperidine

The title compound was obtained in the same manner as in Reference Example 23, Step 1, using piperidine instead of morpholine.

¹ H-NMR (CDCl ₃ )?: 6.34 (2H, d, J = 11.4 Hz), 3.37 (1H, s), 3.26-3.20 (4H, m), 1.68-1.60 (6H, m). LCMS (ESI) m / z 222 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 102

According to Reference Example 93, Step 10, using 1- (4-ethynyl-3,5-difluorophenyl) piperidine instead of 1-ethynylnaphthalene, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.57 (1H, s), 6.54 (2H, d, J = 11.7㎐), 4.98-4.91 (1H, m), 4.40 (1H, m), 3.28-3.14 (2H, m), 2.48-2.39 (1H, m), 4.01 (1H, dd, J = , 2.35-2.26 (1H, m), 1.85-1.75 (1H, m), 1.70-1.63 (6H, m). LCMS (ESI) m / z 562 [M + H] &lt; ⁺ &gt;.

Reference Example 103

Ethynyl] -7 - [(1R, 2S, 3R, 4R) - (4-methylpiperazin- 2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) -4-methylpiperazine Synthesis of 1-

According to Reference Example 23, Step 1, 4-methylpiperazine was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.36 (2H, d, J = 11.0㎐), 3.39 (1H, s), 3.27-3.23 (4H, m), 2.54-2.50 (4H, m), 2.34 (3H , s). LCMS (ESI) m / z 237 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 103

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (4-ethynyl-3,5-difluorophenyl) -4-methylpiperazine instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.76 (1H, s), 6.76 (2H, d, J = 10.6㎐), 5.06-4.97 (1H, m), 4.40 (1H, (1H, d, J = 8.6, 5.6 Hz), 4.01 (1H, dd, J = 5.6, 3.7 Hz), 3.49-3.11 (10H, m), 2.97 -2.26 (1 H, m), 1.87-1.77 (1 H, m). LCMS (ESI) m / z 577 [M + H] &lt; ⁺ &gt;.

Reference Example 104

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2, 2-dihydro- 3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4 - ((1H-pyrazol-1-yl) methoxy) -2,6-difluorobenzaldehyde

According to Reference Example 55, Step 1, 2,6-difluoro-4-hydroxybenzaldehyde and 1- (chloromethyl) pyrazole hydrochloride were used instead of 2-fluoro-6-hydroxybenzaldehyde and iodoethane To obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 10.20 (1H, s), 7.65-7.62 (2H, m), 6.81 (2H, d, J = 10.0 Hz), 6.39 6.05 (2 H, s). LCMS (ESI) m / z 239 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 1 - ((4-ethynyl-3,5-difluorophenoxy) methyl) -1H-pyrazole

By using 4 - ((1H-pyrazol-1-yl) methoxy) -2,6-difluorobenzaldehyde in place of 2-fluoro-6-methoxybenzaldehyde according to Reference Example 51, The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.64-7.60 (2H, m), 6.73 (2H, d, J = 8.8㎐), 6.37 (1H, t, J = 2.2㎐), 5.99 (2H, s), 3.42 (1 H, s). LCMS (ESI) m / z 235 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 104

The title compound was obtained by using 1 - ((4-ethynyl-3,5-difluorophenoxy) methyl) -1H-pyrazole instead of 1-ethynylnaphthalene according to Reference Example 93, Step 10 .

^{1 H-NMR (DMSO-D} 6) δ: 8.14 (1H, s), 8.04 (1H, d, J = 2.0㎐), 7.91 (1H, s), 7.61 (1H, d, J = 1.5㎐), M), 6.18 (2H, s), 4.91-4.86 (2H, s), 7.15 (2H, d, J = 9.5 Hz), 6.64 (2H, m), 4.69-4.66 (1H, brs), 4.23-4.19 (1H, m), 3.80-3.77 (1H, brs), 3.09-3.04 , 2.26-2.18 (1H, m), 2.14-2.10 (1H, m), 1.59-1.51 (1H, m). LCMS (ESI) m / z 575 [M + H] &lt; ⁺ &gt;.

Reference Example 105

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2,3 &lt; RTI ID = 0.0 & - dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) pyrrolidine

According to Reference Example 23, Step 1, pyrrolidine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 6.02 (2H, d, J = 10.6 Hz), 3.38 (1H, s), 3.28-3.22 (4H, m), 2.04-2.00 (4H, m). LCMS (ESI) m / z 208 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 105

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (4-ethynyl-3,5-difluorophenyl) pyrrolidine instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.54 (1H, s), 6.21 (2H, d, J = 11.0㎐), 4.40 (1H, dd, J = 8.6, 5.7㎐) , 4.00 (1H, t, J = 4.6 Hz), 3.67-3.62 (1H, m), 3.29-3.05 (6H, m), 2.48-2.39 -2.02 (4 H, m), 1.85 - 1.75 (1 H, m). LCMS (ESI) m / z 548 [M + H] &lt; ⁺ &gt;.

Reference Example 106

[(2R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] 6-fluoro-4- (1-piperidyl) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (3-ethoxy-4-ethynyl-5-fluorophenyl) piperidine

(4-ethynyl-3,5-difluorophenyl) piperidine was used instead of 4- (4-ethynyl-3,5-difluorophenyl) morpholine in accordance with Referential Example 34, , The title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 6.24 (1H, dd, J = 12.8, 2.2㎐), 6.18-6.16 (1H, m), 4.12 (2H, q, J = 7.0㎐), 3.42 (1H, s ), 3.27-3.22 (4H, m), 1.73-1.60 (6H, m), 1.48 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 248 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 106

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (3-ethoxy-4-ethynyl-5-fluorophenyl) piperidine instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.50 (1H, s), 6.33-6.30 (2H, m), 4.97-4.90 (1H, m), 4.39 (1H, dd, J M), 2.47-2.40 (1 H, m), 4.17 (2H, q, J = 7.1 Hz), 4.00 (1H, dd, J = 5.7, 3.8 Hz) , 2.34-2.26 (1H, m), 1.84-1.75 (1H, m), 1.71-1.61 (6H, m), 1.45 (3H, t, J = 7.1 Hz). LCMS (ESI) m / z 588 [M + H] &lt; ⁺ &gt;.

Reference Example 107

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2,3-dihydroxy-isoquinolin- 4 - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4- (benzyloxy) -2,6-difluorobenzaldehyde

According to Reference Example 55, Step 1, the title compound was obtained by using 2,6-difluoro-4-hydroxybenzaldehyde and benzyl bromide instead of 2-fluoro-6-hydroxybenzaldehyde and iodoethane.

¹ H-NMR (CDCl ₃ )?: 10.20 (1H, s), 7.49-7.36 (5H, m), 6.57 (2H, d, J = 10.5 Hz), 5.11 (2H, s). LCMS (ESI) m / z 249 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 5- (benzyloxy) -2-ethynyl-1,3-difluorobenzene

According to Reference Example 51, Step 1, using 4- (benzyloxy) -2,6-difluorobenzaldehyde instead of 2-fluoro-6-methoxybenzaldehyde, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.41-7.36 (5H, m), 6.54 (2H, d, J = 9.0 Hz), 5.04 (2H, s), 3.42 (1H, s). LCMS (ESI) m / z 245 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 107

According to Reference Example 93, Step 10, 5- (benzyloxy) -2-ethynyl-1,3-difluorobenzene was used in place of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.15 (1H, s), 7.63 (1H, s), 7.45-7.34 (5H, m), 6.78 (2H, d, J = 9.5㎐), 5.13 (2H, (2H, m), 2.46-2.40 (1H, m), 2.31-2.40 (1H, m) 2.28 (1 H, m), 1.83-1.78 (1 H, m). LCMS (ESI) m / z 585 [M + H] &lt; ⁺ &gt;.

Reference Example 108

4 - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2, 3-dihydroxy- 2,3-d] pyrimidin-5-yl] ethynyl] -3-ethoxy-5-fluoro-phenyl] -8-oxa-3-azabicyclo [

(Step 1) Synthesis of 3- (4-ethynyl-3,5-difluorophenyl) -8-oxa-3-azabicyclo [3.2.1]

Oxa-3-azabicyclo [3.2.1] octane was used instead of morpholine in accordance with Referential Example 23, Step 1, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 6.28 (2H, dd, J = 13.9, 2.9 Hz), 4.52-4.49 (2H, m), 3.40 ), 3.08 (2H, dd, J = 11.3, 2.7 Hz), 2.04-1.96 (2H, m), 1.89-1.82 (2H, m). LCMS (ESI) m / z 250 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 3- (3-ethoxy-4-ethynyl-5-fluorophenyl) -8-oxa- 3-azabicyclo [3.2.1]

According to Reference Example 34, Step 1, 3- (4-ethynyl-3,5-difluorophenyl) -8- Oxa-3-azabicyclo [3.2.1] octane, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 6.12 (1H, dd, J = 12.6, 2.4㎐), 6.03 (1H, s), 4.51-4.47 (2H, m), 4.09 (2H, q, J = 7.0㎐ ), 3.40 (1H, s), 3.28 (2H, d, J = 11.3 Hz), 3.06 (2H, dd, J = 11.3, 2.7 Hz), 2.03-1.92 m), 1.46 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 276 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 108

According to the same manner as in Reference Example 93, Step 10, 3- (3-ethoxy-4-ethynyl-5-fluorophenyl) -8-oxa- 3-azabicyclo [3.2.1] octane , The title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.12 (1H, s), 7.49 (1H, s), 6.29 (1H, d, J = 1.8㎐), 6.25 (1H, s), 4.94-4.90 (1H, d, J = 5.7, 3.8 Hz), 4.47 (2H, s), 4.39 (1H, dd, J = 8.4, 5.9 Hz) Dd, J = 11.5 Hz), 3.97 (2H, d, J = 11.0 Hz), 3.26 (1H, dd, J = M), 1.84-1.74 (1H, m), 1.45 (3H, t, J = 7.0 Hz), 2.48-2. ). LCMS (ESI) m / z 616 [M + H] &lt; ⁺ &gt;.

Reference Example 109

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2,3-dihydroxy-4H- - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 2,3-dihydrobenzo [b] thiophene-7-carbaldehyde

(200 mg, 0.93 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of n-butyllithium (1.6 M hexane solution, 1.4 mL, 2.2 mmol), which was stirred for 30 minutes at -78 ° C. Subsequently, N, N-dimethylformamide (0.22 mL, 2.8 mmol) was added at -78 ° C, and the mixture was stirred at -78 ° C for 20 minutes and then at room temperature for 1 hour. Saturated ammonium chloride aqueous solution, water and ethyl acetate were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (74 mg, 49%) as a yellow oily substance.

_{^{1 H-NMR (CDCl 3)}} δ: 10.05 (1H, s), 7.62 (1H, d, J = 7.5㎐), 7.39 (1H, dd, J = 7.5, 1.0㎐), 7.18 (1H, t, J = 7.5 Hz), 3.42-3.37 (2H, m), 3.31 (2H, t, J = 7.6 Hz). LCMS (ESI) m / z 165 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 7-ethynyl-2,3-dihydrobenzo [b] thiophene

According to Reference Example 51, Step 1, 2,3-dihydrobenzo [b] thiophene-7-carbaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to give the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.25 (1H, d, J = 7.6㎐), 7.15 (1H, dd, J = 7.6, 1.0㎐), 6.96 (1H, t, J = 7.6㎐), 3.40- 3.31 (5 H, m).

(Step 3) Reference Example Synthesis of Compound 109

According to Reference Example 93, Step 10, 7-ethynyl-2,3-dihydrobenzo [b] thiophene was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.15 (1H, s), 7.60 (1H, s), 7.23 (1H, d, J = 7.6㎐), 7.20-7.17 (1H, m), 7.02 (1H, (1H, dd, J = 7.6, 7.6 Hz), 4.97-4.88 (1H, m), 4.43-4.40 (1H, m), 4.02-4.00 (1H, m), 3.44-3.34 1H, m), 3.20-3.15 (1H, m), 2.48-2.41 (1H, m), 2.32-2.28 (1H, m), 1.86-1.78 (1H, m). LCMS (ESI) m / z 501 [M + H].

Reference Example 110

4 - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2, 3-dihydroxy- 2,3-d] pyrimidin-5-yl] ethynyl] -3-ethoxy-5-fluoro-phenyl] -3-oxa-8- azabicyclo [

(Step 1) Synthesis of 8- (4-ethynyl-3,5-difluorophenyl) -3-oxa-8-azabicyclo [3.2.1]

According to Reference Example 23, Step 1, 3-oxa-8-azabicyclo [3.2.1] octane was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.23 (2H, dd, J = 13.6, 3.3㎐), 4.01-3.98 (2H, m), 3.81 (2H, d, J = 11.2㎐), 3.53 (2H, d , J = 11.2 Hz), 3.39 (1H, s), 2.16-2.01 (4H, m). LCMS (ESI) m / z 250 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 8- (3-ethoxy-4-ethynyl-5-fluorophenyl) -3-oxa-8- azabicyclo [3.2.1]

According to Reference Example 34, Step 1, 8- (4-ethynyl-3,5-difluorophenyl) -3- (4-ethynyl-3,5-difluorophenyl) Oxa-8-azabicyclo [3.2.1] octane, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 6.08 (1H, dd, J = 12.1, 2.2㎐), 6.00 (1H, s), 4.08 (2H, q, J = 7.0㎐), 4.01 (2H, d, J J = 11.0 Hz), 3.39 (1H, d, J = 5.9 Hz), 2.13-2.00 (4H, m) 1.45 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 276 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 110

According to Reference Example 93, Step 10, 8- (3-ethoxy-4-ethynyl-5-fluorophenyl) -3-oxa-8- azabicyclo [3.2.1] octane , The title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.50 (1H, s), 6.29 (1H, d, J = 2.2㎐), 6.25 (1H, d, J = 2.2㎐), 4.97 4.9 (1H, m), 4.39 (1H, dd, J = 8.4, 5.8 Hz), 4.21-4.14 (4H, m), 4.01 (2H, m), 2.49-2.39 (1H, m), 2.35-2.26 (1H, m), 2.10-1.99 4H, m), 1.85-1.75 (1H, m), 1.45 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 616 [M + H] &lt; ⁺ &gt;.

Reference Example 111

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- [ -4- (1-piperidyl) phenyl] ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 4-fluoro-2- (methylthio) benzaldehyde

Sodium thiomethoxide (680 mg, 9.6 mmol) was suspended in toluene (10 mL), 2,4-difluorobenzaldehyde (1 g, 7.0 mmol) was added and the mixture was stirred at 80 ° C for 2 days. Ethyl acetate and water were added to the reaction solution, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (499 mg, 42%) as a white solid.

¹ H-NMR (CDCl ₃ )?: 10.15 (1H, s), 7.82 (1H, dd, J = 8.3, 6.1 Hz), 7.01 (1H, dd, J = 10.1, 2.3 Hz) , J = 2.3, 8.3 Hz), 2.49 (3H, s). LCMS (ESI) m / z 171 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 2- (methylthio) -4- (piperidin-1-yl) benzaldehyde

(200 mg, 1.2 mmol) and potassium carbonate (220 mg, 1.6 mmol) were suspended in dimethyl sulfoxide (2 mL), and piperidine (0.16 ml, 1.6 mmol) were added, and the mixture was stirred at 80 占 폚 for 2 hours and 30 minutes. Ethyl acetate and water were added to the reaction solution at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (345 mg) as a yellow oily substance.

_{^{1 H-NMR (CDCl 3)}} δ: 9.99 (1H, s), 7.64 (1H, d, J = 8.7㎐), 6.68 (1H, dd, J = 8.7, 2.3㎐), 6.64 (1H, d, J = 2.3 Hz), 3.43-3.40 (4H, m), 2.47 (3H, s), 1.80-1.70 (6H, m). LCMS (ESI) m / z 236 [M + H] &lt; ^{+ &}

(Step 3) Synthesis of 1- (4-ethynyl-3- (methylthio) phenyl) piperidine

According to Reference Example 51, Step 1, 2- (methylthio) -4- (piperidin-1-yl) benzaldehyde was used instead of 2-fluoro-6-methoxybenzaldehyde to give the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.32 (1H, d, J = 8.6㎐), 6.68 (1H, d, J = 2.5㎐), 6.63 (1H, dd, J = 8.6, 2.5㎐), 3.35 ( 1H, s), 3.24-3.21 (4H, m), 2.49 (3H, s), 1.72-1.58 (6H, m). LCMS (ESI) m / z 232 [M + H] &lt; ^{+ &}

(Step 4) Reference Example Synthesis of Compound 111

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (4-ethynyl-3- (methylthio) phenyl) piperidine instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.53 (1H, s), 7.29 (1H, d, J = 8.8㎐), 6.81 (1H, d, J = 2.3㎐), 6.75 (1H, dd, J = 8.8,2.3 Hz), 4.96-4.87 (1H, m), 4.42-4.38 (1H, m), 4.02-4.00 (3H, s), 2.48-2.40 (1H, m), 2.28-2.32 (1H, m), 1.85-1.77 (1H, m), 1.72-1.61 (6H, m). LCMS (ESI) m / z 572 [M + H].

Reference Example 112

4 - [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2, 3-dihydroxy- 2,3-d] pyrimidin-5-yl] ethynyl] -3-ethoxy-5- fluoro-phenyl]

According to Reference Example 93, Step 10, the title compound was obtained by using 4- (3-ethoxy-4-ethynyl-5-fluorophenyl) morpholine in place of 1-ethynylnaphthalene.

^{1 H-NMR (DMSO-D} 6) δ: 8.12 (1H, s), 7.73 (1H, s), 6.65 (1H, t, J = 6.0㎐), 6.56-6.39 (4H, m), 4.91-4.84 (2H, m), 4.69 (1H, d, J = 4.4 Hz), 4.23-4.16 (2H, m), 3.79 (1H, dd, J = 8.4,4.4Hz), 3.74-3.68 M), 2.15-2.07 (2H, m), 1.60-1.51 (1H, m), 3.26-3.21 (4H, m), 3.12-3.04 , &lt; / RTI &gt; m), 1.36 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 590 [M + H] &lt; ⁺ &gt;.

Reference Example 113

Cyclopentyl] -5- [2- (4-methoxy-phenyl) -4-methyl- 2-methylsulfonyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of triisopropyl ((4-methoxy-2- (methylsulfonyl) phenyl) ethynyl) silane

According to the reference example 76, step 2, using 1-bromo-2-methanesulfonyl-4-methoxybenzene instead of 5- (benzyloxy) -2-bromopyrimidine, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.61-7.59 (2H, m), 7.06 (1H, dd, J = 8.5, 2.7㎐), 3.88 (3H, s), 3.33 (3H, s), 1.19-1.12 (21H, m). LCMS (ESI) m / z 367 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 1-ethynyl-4-methoxy-2- (methylsulfonyl) benzene

((4-methoxy-2- (methylsulfonyl) phenyl) phenylmethanesulfonamide was used in place of 5- (benzyloxy) -2 - ) Ethynyl) silane, the title compound was obtained.

_{^{1 H-NMR (CDCl 3)}} δ: 7.64-7.62 (2H, m), 7.09 (1H, dd, J = 8.5, 2.7㎐), 3.90 (3H, s), 3.53 (1H, s), 3.31 (3H , s). LCMS (ESI) m / z 211 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 113

According to Reference Example 93, Step 10, 1-ethynyl-4-methoxy-2- (methylsulfonyl) benzene was used instead of 1-ethynylnaphthalene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.16 (1H, s), 7.72 (1H, s), 7.70 (1H, d, J = 8.6㎐), 7.57 (1H, d, J = 2.8㎐), 7.26 (1H, dd, J = 8.6, 2.8 Hz), 4.99-4.91 (1H, m), 4.44-4.40 (1H, m), 4.03-4.01 (1H, m), 3.39-3.24 (1H, m), 3.21-3.16 (1H, m), 2.50-2.42 (1H, m), 2.35-2.28 LCMS (ESI) m / z 551 [M + H].

Reference Example 114

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- -6-fluoro-4-pyrrolidin-l-yl-phenyl) ethynyl] pyrrolo [2,3- d] pyrimidine

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (3- (ethylsulfonyl) -4-ethynyl-5-fluorophenyl) pyrrolidine instead of 1- ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.13 (1H, s), 7.62 (1H, s), 6.99 (1H, d, J = 2.6㎐), 6.64 (1H, dd, J = 12.4, 2.6㎐) (1H, m), 4.98-4.90 (1H, m), 4.43-4.39 (1H, m), 4.02-4.00 M), 2.09-2.06 (4H, m), 1.85-1.77 (1 H, m), 2.34-2.28 (1 H, m) m), 1.24 (3H, t, J = 7.4 Hz). LCMS (ESI) m / z 622 [M + H].

Reference Example 115

Yl] phenyl] ethynyl] -7 - [(1R, 2S (3R) -3-fluoropyrrolidin- , 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3- d] pyrimidine

By using (3R) -1- (4-ethynyl-3,5-difluorophenyl) -3-fluoropyrrolidine instead of 1-ethynylnaphthalene according to Reference Example 93, Step 10, Compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.12 (1H, s), 7.54 (1H, s), 6.25 (2H, d, J = 10.6㎐), 5.38 (1H, d, J = 53.2㎐), 5.04 Dd, J = 5.5, 3.7 Hz), 3.64-3.10 (6H, m), 2.49-2.38 (1H, m), 2.37-2.26 (2H, m), 2.22-2.12 (1H, m), 1.84-1.75 (1H, m). LCMS (ESI) m / z 566 [M + H] &lt; ⁺ &gt;.

Reference Example 116

Yl] phenyl] ethynyl] -7 - [(1R, 2S (3R) -3-fluoropyrrolidin- , 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of (3S) -1- (4-ethynyl-3,5-difluorophenyl) -3-fluoropyrrolidine

According to Reference Example 23, Step 1, (S) -3-fluoropyrrolidine was used instead of morpholine to obtain the title compound.

¹ H-NMR (CDCl ₃ )?: 6.06 (2H, d, J = 10.3 Hz), 5.38 (1H, d, J = 53.5 Hz), 3.62-3.39 (5H, m), 2.47-2.36 ), 2.28-2.07 (1 H, m). LCMS (ESI) m / z 226 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 116

By using (3S) -1- (4-ethynyl-3,5-difluorophenyl) -3-fluoropyrrolidine instead of 1-ethynylnaphthalene according to Reference Example 93, Step 10, Compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.11 (1H, s), 7.53 (1H, s), 6.22 (2H, d, J = 10.6㎐), 5.38 (1H, d, J = 53.2㎐), 4.93 (1H, m), 2.34 (1H, d, J = 5.5, 4.0 Hz), 3.42-3.15 (6H, m), 2.49-2.40 -2.27 (2H, m), 2.22-2.08 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m / z 566 [M + H] &lt; ⁺ &gt;.

Reference Example 117

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- Oxo-2,3-dihydrobenzothiophen-7-yl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 7-ethynyl-2,3-dihydrobenzo [b] thiophene 1,1-dioxide

According to Reference Example 70, Step 3, 7-ethynyl-2,3-dihydrobenzo [b] thiophene was used in the place of 2- (ethylthio) -6-fluoro-4- (pyrrolidin- Thiophene, the title compound was obtained.

¹ H-NMR (CDCl ₃ )?: 7.57-7.51 (2H, m), 7.36 (1H, d, J = 7.1 Hz), 3.57-3.52 (3H, m), 3.35 ). LCMS (ESI) m / z 193 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 117

According to Reference Example 93, Step 10, the title compound was obtained by using 7-ethynyl-2,3-dihydrobenzo [b] thiophene 1,1-dioxide instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.15 (1H, s), 7.74 (1H, s), 7.64 (1H, t, J = 7.6㎐), 7.58 (1H, d, J = 7.6㎐), 7.45 (1H, d, J = 7.6 Hz), 5.00-4.89 (1H, m), 4.44-4.40 (1H, m), 4.03-4.00 3.41 (2H, t, J = 7.1 Hz), 3.22-3.11 (2H, m), 2.48-2.42 (1H, m), 2.32-2.26 (1H, m), 1.87-1.77 (1H, m). LCMS (ESI) m / z 533 [M + H].

Reference Example 118

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2, 6-difluoro-phenyl] 3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (4-ethynyl-3,5-difluorophenyl) azetidine in place of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.14 (1H, s), 7.56 (1H, s), 6.03 (2H, d, J = 10.0㎐), 4.99-4.89 (1H, m), 4.40 (1H, dd, J = 8.5,5.6 Hz), 4.01 (1H, dd, J = 5.6, 3.7 Hz), 3.94 (4H, t, J = 7.4 Hz), 3.28-3.09 (2H, m), 2.46-2.36 , &lt; / RTI &gt; m), 2.34-2.24 (1H, m), 1.85-1.72 (1H, m). LCMS (ESI) m / z 534 [M + H] &lt; ⁺ &gt;.

Reference Example 119

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -4-amino-5- [2- [2,6-difluoro- -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of 1- (4-ethynyl-3,5-difluorophenyl) piperidin-4-ol

The title compound was obtained in the same manner as in Reference Example 23, Step 1, using piperidin-4-ol instead of morpholine.

_{^{1 H-NMR (CDCl 3)}} δ: 6.36 (2H, d, J = 11.2㎐), 3.93-3.87 (1H, m), 3.58 (2H, dt, J = 13.0, 4.9㎐), 3.40 (1H, s ), 3.06-3.00 (2H, m), 2.21-2.10 (1H, m), 1.99-1.91 (2H, m), 1.65-1.55 (2H, m). LCMS (ESI) m / z 238 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 119

According to Reference Example 93, Step 10, the title compound was obtained by using 1- (4-ethynyl-3,5-difluorophenyl) piperidin-4-ol instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.19 (1H, s), 7.57 (1H, s), 6.57 (2H, d, J = 11.5㎐), 4.98-4.89 (1H, m), 4.40 (1H, m), 3.30-3.14 (2H, m), 3.08 (1H, d, J = 6.3 Hz), 4.01 (1H, dd, J = 5.5, 3.8 Hz), 3.85-3.78 M), 1.60-1.50 (2H, m), 1.00-1.40 (2H, m) m). LCMS (ESI) m / z 578 [M + H] &lt; ⁺ &gt;.

Reference Example 120

Yl] phenyl] ethynyl] -7 - [(1R, 2S) -3-hydroxypyrrolidin- , 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3- d] pyrimidine

(3R) -1- (4-ethynyl-3,5-difluorophenyl) -pyrrolidin-3-ol was used in place of 1-ethynylnaphthalene according to Reference Example 93, Step 10, Compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.22 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J = 11.0㎐), 4.98-4.90 (1H, m), 4.55-4.51 ( (2H, m), 3.40-3.33 (1H, m), 3.27-3.14 (1H, m), 4.43-4.36 M), 2.48-2.40 (1H, m), 2.34-2.26 (1H, m), 2.20-2.09 (1H, m), 2.08-2.00 (1H, m), 1.84-1.75 (1H, m). LCMS (ESI) m / z 564 [M + H] &lt; ⁺ &gt;.

Reference Example 121

Yl] phenyl] ethynyl] -7 - [(1R, 2S (3R) -3-hydroxypyrrolidin- , 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3- d] pyrimidine

(Step 1) Synthesis of (3S) -1- (4-ethynyl-3,5-difluorophenyl) -pyrrolidin-3-ol

According to Reference Example 23, Step 1, (S) -pyrrolidin-3-ol was used instead of morpholine to obtain the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 6.03 (2H, d, J = 10.5㎐), 4.64-4.60 (1H, m), 3.51-3.43 (2H, m), 3.39 (1H, s), 3.34 (1H , dt, J = 3.2, 9.0 Hz), 3.22 (1H, d, J = 10.7 Hz), 2.22-2.12 (1H, m), 2.12-2.05 (1H, m). LCMS (ESI) m / z 224 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 121

By using (3S) -1- (4-ethynyl-3,5-difluorophenyl) -pyrrolidin-3-ol instead of 1-ethynylnaphthalene according to Reference Example 93, Step 10, Compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.23 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J = 10.7㎐), 4.97-4.89 (1H, m), 4.54-4.49 ( (1H, m), 4.46-4.35 (1H, m), 4.03-3.96 (1H, m), 3.51-3.41 2.48-2.39 (1H, m), 2.35-2.25 (1H, m), 2.19-2.09 (1H, m), 2.08-2.00 (1H, m), 1.84-1.74 (1H, m). LCMS (ESI) m / z 564 [M + H] &lt; ⁺ &gt;.

Reference Example 122

Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-

(Step 1) According to Reference Example 93, Step 10, 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine was used instead of 1- To obtain the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.17-8.12 (2H, m), 7.84 (1H, s), 6.77-6.64 (3H, m), 6.53 (2H, s), 4.88 (1H, dd, J = 18.7, 8.4 Hz), 4.43 (2H, t, J = 4.2 Hz), 4.21 (1H, dd, J = 8.6, 5.3 Hz), 3.80 (2H, t, J = 4.2 Hz), 3.12-3.04 (1H, m), 2.96-2.89 (1H, m), 2.82 m), 1.56 (1 H, dd, J = 20.9, 11.0 Hz). LCMS (ESI) m / z 532.3 [M + H] &lt; ⁺ &gt;.

(Step 2) To a solution of 8- [2- [4-amino-7 - [(1R, 2S, 3R, 4R) -2,3-dihydroxy- [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine hydrochloride

The title compound hydrochloride was obtained in accordance with Referential Example 1, Step 5.

^{1 H-NMR (DMSO-D} 6) δ: 8.45 (1H, s), 8.24 (1H, s), 6.81-6.74 (2H, m), 4.98 (1H, dd, J = 19.1, 8.8㎐), 4.47 (2H, t, J = 4.2 Hz), 4.20 (1H, dd, J = 9.0, 5.3 Hz), 3.80 (1H, dd, J = 5.1, 2.9 Hz), 3.27 , 3.08 (1H, dd, J = 12.8, 6.6 Hz), 2.93 (1H, dd, J = 12.5, 7.3 Hz), 2.84 (3H, s), 2.29-2.22 , &lt; / RTI &gt; m), 1.58 (1H, dd, J = 20.7, 10.8 Hz). LCMS (ESI) m / z 532.4 [M + H] &lt; ^{+ &}

Reference Example 123

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- Oxo-3,4-dihydro-2H-thiochromen-8-yl) ethynyl] pyrrolo [2,3- d] pyrimidine

According to Reference Example 93, Step 10, the title compound was obtained by using 8-ethynylthiocromethane 1,1-dioxide instead of 1-ethynylnaphthalene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.16 (1H, s), 7.73 (1H, s), 7.57 (1H, d, J = 7.7㎐), 7.50 (1H, t, J = 7.7㎐), 7.31 (1H, d, J = 7.7 Hz), 5.03-4.89 (1H, m), 4.44-4.40 (1H, m), 4.04-4.02 (1H, m), 3.22-3.17 (1H, m), 3.09 (2H, t, J = 6.0Hz), 2.50-2.39 (3H, m), 2.36-2.27 , m). LCMS (ESI) m / z 547 [M + H].

Reference Example 124

Ethyl-7 - [(2R, 4S, 5R) -4-hydroxy-5 - [(sulfamoylamino) methyl] tetra 2-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) (2R, 3S, 5R) -5- (4-Amino-5-iodo-7H- pyrrolo [2,3- d] pyrimidin- Synthesis of hydrofuran-3-ol

Pyrrolo [2,3-d] pyrimidin-7-yl) -2 (1 H) -quinolinone (2R, 3S, 5R) -5- (4-tert-butoxycarbonylamino) -Amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin- 7-yl) -2- (hydroxymethyl) tetrahydrofuran-3-ol was used to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.09 (1H, s), 7.48 (1H, s), 6.52 (1H, t, J = 7.0㎐), 4.37 (1H, dt, J = 6.6, 4.0㎐) , 3.89 (1H, dt, J = 7.0, 4.0 Hz), 2.91 (1H, dd, J = 13.2, 4.0 Hz), 2.83 ), 2.33 (1H, ddd, J = 13.9, 7.0, 3.7 Hz). LCMS (ESI) m / z 376 [M + H] &lt; ^{+ &}

(Step 2) To a solution of tert-butyl N - [[(2R, 3S, 5R) -5- (4-amino- Hydroxy-tetrahydrofuran-2-yl] methylsulfamoyl] carbamate

3,4-d] [l, 3] di (tert-butoxycarbonyl) amino] -2,3- (2R, 3S, 5R) -5- (4-amino-5-iodo-pyridin- -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- (aminoethyl) tetrahydrofuran-3-ol was used to yield the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 10.84 (1H, s), 8.09 (1H, s), 7.61 (1H, s), 6.76-6.61 (2H, brm), 6.35 (1H, dd, J = M), 3.16-3.10 (2H, m), 2.59-2.52 (1H, d, J = 4.0 Hz), 4.28-4.26 , &lt; / RTI &gt; m), 2.11-2.06 (1H, m), 1.36 (9H, s). LCMS (ESI) m / z 555 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 124

pyrrolo [2,3-d] pyrimidin-7-yl) -3-hydroxy-isoquinoline- Yl) methylsulfamoyl] carbamate (40 mg, 0.072 mmol), 2-ethynyl-1,3-difluorobenzene (15 mg, 0.11 mmol), bis (triphenylphosphine ) Palladium (II) dichloride (10 mg, 0.014 mmol), copper iodide (2.7 mg, 0.014 mmol) and diisopropylethylamine (0.030 mL, 0.18 mmol) were suspended in tetrahydrofuran (0.5 mL). After the reaction solution was stirred overnight at 70 ° C, trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (1.2 mg, 4%) as a white powder.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 8.00 (1H, s), 7.53-7.47 (1H, m), 7.29-7.24 (1H, m), 7.18-7.15 (1H, (1H, m), 6.58 (2H, s), 6.43 (1H, dd, J = 8.8, 5.6 Hz), 5.35 (1H, d, J = 4.1 Hz), 4.39-4.35 , br m), 3.18-3.03 (2H, br m), 2.66-2.59 (1 H, m). LCMS (ESI) m / z 465 [M + H] &lt; ⁺ &gt;.

Reference Example 125

2-yl] -5- [2- (1-naphthyl) -4-hydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 124, Step 3, using 1-ethynylnaphthalene instead of 2-ethynyl-1,3-difluorobenzene, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.39 (1H, d, J = 8.4㎐), 8.35 (1H, s), 8.07 (1H, s), 7.96 (1H, brs), 7.94 (1H, brs) , 7.85 (1H, d, J = 7.3 Hz), 7.67-7.46 (3H, m), 6.59 (1H, dd, J = 7.7, 6.2 Hz), 4.62-4.59 (1H, ddd, J = 13.9, 7.7, 6.2 Hz), 2.45 (1H, ddd, J = 13.9, 6.2, 2.9 Hz). LCMS (ESI) m / z 479 [M + H] &lt; ⁺ &gt;.

Reference Example 126

Yl] pyrrolo [2,3-d] pyrimidine-4-carboxylic acid ethyl ester was obtained in the same manner as in [ 5-yl] -2- (o-tolyl) thiazole

Pyrrolo [2,3-d] pyrimidin-7 (3R) -7- (4-fluoropyridin-2-yl) Tert-butyl-N - [[(2R) -2,3-dimethyl-tetrahydrofuro [3,4- d] [1,3] dioxol-4- yl) methyl) sulfamoylcarbamate , 3S, 5R) -5- (4-Amino-5-iodo-pyrrolo [2,3- d] pyrimidin-7-yl) -3-hydroxy-tetrahydrofuran- Yl] carbamate, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.37 (1H, s), 8.26 (1H, s), 8.15 (1H, s), 8.04-8.01 (1H, m), 7.66 (1H, d, J = 7.7 (1H, dt, J = 5.9, 3.3 Hz), 3.44 (1H, d, J = 7.7, 6.2 Hz), 7.49-7.35 (1H, dd, J = 13.6, 4.0 Hz), 3.39 (1H, dd, J = 13.6, 4.8 Hz), 2.72-2.65 = 13.6, 6.2, 3.3 Hz). LCMS (ESI) m / z 502 [M + H] &lt; ⁺ &gt;.

Reference Example 127

Ethyl-7 - [(2R, 4S, 5R) -4-hydroxy-5 - [(sulfamoylamino) Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 124, Step 3, the title compound was obtained by using 1-ethoxy-2-ethynyl-3-fluorobenzene instead of 2-ethynyl-1,3-difluorobenzene.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.88 (1H, s), 7.37 (1H, ddd, J = 8.8, 8.4, 7.0㎐), 7.19 (1H, dd, J = Dd, J = 8.4, 5.5 Hz), 6.97 (1H, d, J = 8.4 Hz) (1H, m), 5.37 (1H, d, J = 4.0 Hz), 4.37 2.67-2.61 (1H, m), 2.17 (1H, dd, J = 13.6, 5.5 Hz), 1.37 (3H, t, J = 7.0 Hz). LCMS (ESI) m / z 491 [M + H] &lt; ⁺ &gt;.

Reference Example 128

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) Methyl] cyclopent-2-en-1-yl] pyrrolo [2,3-d] pyrimidine

(Step 1) ((3aS, 4R, 6aR) -6 - (((tert-Butyldiphenylsilyl) oxy) methyl) -2,2- dimethyl-4,6a-dihydro-3aH- cyclopenta [d] [1,3] dioxol-4-ol

(3aR, 6aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2,2-dimethyl- 3aH-cyclopenta [d] [1,3] dioxol- (92%, 146 mg, 3.54 mmol) was suspended in methanol (5 mL) at 0 ° C while stirring, to which was then added potassium cyanide Respectively. After stirring at 0 DEG C for 2 hours, water (20 mL) was added, acetic acid was added until the reaction solution became about 5 pH, and the reaction solution was partitioned between ethyl acetate and water, and the organic layer was separated. The obtained organic layer was washed successively with a saturated aqueous solution of ammonium chloride and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to obtain the title compound Mg) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ )?: 7.72-7.66 (4H, m), 7.45-7.37 (6H, m), 5.85 d, J = 6.2, 5.9 Hz), 4.58-4.55 (1H, brm), 4.39 (1H, d, J = 14.7 Hz), 4.29 , 1.34 (3 H, s), 1.08 (9 H, s). LCMS (ESI) m / z 425 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of 7 - ((3aS, 4R, 6aR) -6- (((tert- butyldiphenylsilyl) oxy) methyl) -2,2- dimethyl- 4,6a- dihydro- 3aH-cyclopenta [ d] [1,3] dioxol-4-yl) -4-chloro-5-iodo-7H-pyrrolo [2,3- d] pyrimidine

(3aS, 4R, 6aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2,2- dimethyl- 4,6a-dihydro-3aH- cyclopenta [ 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (632 mg, 2.26 mmol), triphenylphosphine (889 mg, Was dissolved in tetrahydrofuran (7 mL), and diisopropyl azodicarboxylate (667 μL, 3.39 mmol) was added dropwise at 0 ° C. while stirring. The reaction solution was stirred at room temperature for 14 hours, and then the reaction solution was concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (1.33 g) as colorless amorphous substance.

¹ H-NMR (CDCl ₃ )?: 8.69 (1H, s), 7.72-7.69 (4H, m), 7.49-7.39 (2H, d, J = 14.7 Hz), 1.44 (3H, d, J = 5.5 Hz), 5.84-5.82 s), 1.31 (3H, s), 1.11 (9H, s). LCMS (ESI) m / z 687 [M + H] &lt; ^{+ &}

(3R, 6R, 6aS) -6- (4-Amino-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- Synthesis of 6,6a-dihydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol

Dimethyl-4, 6a-dihydro-3aH-cyclopenta [d] [1 (1R) 2,3-d] pyrimidine (16.2 g, 23.6 mmol) was dissolved in 1,4-dioxane (50 mL) And ammonia water (28%, 50 mL), and the mixture was heated and stirred at 100 DEG C for 24 hours using a pressure vessel. After the solvent was distilled off, tetrahydrofuran (50 mL) was added to the residue, tetrabutylammonium fluoride (1M tetrahydrofuran solution, 47 mL) was added at room temperature with stirring, and the mixture was stirred overnight at room temperature. After the reaction solution was partitioned between ethyl acetate and water, the aqueous layer was separated and extracted with ethyl acetate. The organic layer was combined, washed with saturated brine, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (7.4 g) as a milky white solid.

^{1 H-NMR (DMSO-D} 6) δ: 8.12 (1H, s), 7.18 (1H, s), 6.63 (2H, brs), 5.63-5.61 (1H, brm), 5.59-5.59 (1H, brm) D, J = 5.9 Hz), 5.29 (1H, d, J = 5.5 Hz), 5.06 , 1.36 (3H, s), 1.25 (3H, s). LCMS (ESI) m / z 429 [M + H] &lt; ^{+ &}

Pyrrolo [2,3-d] pyrimidin-7-yl) -2, 3-dihydro- Synthesis of 2-dimethyl-6,6a-dihydro-3aH-cyclopenta [d] [1,3] dioxo-4-yl) methyl) (sulfamoyl) carbamate

((3aR, 6R, 6aS) -6- (4-Amino-5-iodo-7H- pyrrolo [2,3- d] pyrimidin- Cyclopenta [d] [1,3] dioxol-4-yl) methanol (100 mg, 0.233 mmol), tert-butylsulfamoylcarbamate (60 mg, 0.30 mmol), triphenylphosphine (92 mg, 0.35 mmol) was dissolved in tetrahydrofuran (1 mL), and diisopropyl azodicarboxylate (69 μL, 0.35 mmol) was added dropwise at 0 ° C. with stirring. The reaction solution was stirred under ice-cooling for 3 hours, methanol (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (60 mg) as colorless amorphous substance.

_{^{1 H-NMR (CDCl 3)}} δ: 8.22 (1H, s), 6.91 (1H, s), 6.36-6.07 (4H, brm), 5.81 (1H, brs), 5.69 (1H, brs), 5.32 (1H , d, J = 5.9 Hz), 4.66-4.52 (3H, m), 1.55 (9H, s), 1.48 (3H, s), 1.34 (3H, s). LCMS (ESI) m / z 607 [M + H] &lt; ^{+ &}

(Step 5) Reference Example Synthesis of Compound 128

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-isoquinolin- Yl) methyl) (sulfamoyl) carbamate (60 mg, 0.099 mmol), 2-ethynyl-l, 3,6-dihydro-3aH-cyclopenta [ (1 mg, 0.0053 mmol) and diisopropylethyl (2-ethylhexyl) borate were added to a solution of 3-difluorobenzene (27.3 mg, 0.198 mmol), bis (triphenylphosphine) palladium Amine (0.034 mL, 0.19 mmol) was suspended in tetrahydrofuran (0.7 mL). After the reaction solution was stirred at 50 DEG C for 1 hour, the reaction solution was concentrated, and the residue was adjusted with silica gel column chromatography (eluent: methanol / chloroform). The obtained residue was dissolved in acetonitrile (0.5 mL) and concentrated hydrochloric acid (0.2 mL) at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (eluent: methanol / chloroform) to give the title compound (5.7 mg, 12%) as a white solid.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.16 (1H, s), 7.56 (1H, s), 7.45-7.38 (1H, m), 7.11-7.05 (2H, m), 5.94 (1H, brs), (1H, d, J = 16.5 Hz), 3.87 (1H, d, J = 1H, d, J = 16.5 Hz). LCMS (ESI) m / z 477 [M + H] &lt; ⁺ &gt;.

Reference Example 129

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 128, Step 5, the title compound was obtained by using 1-ethoxy-2-ethynyl-3-fluorobenzene instead of 2-ethynyl-1,3-difluorobenzene.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.14 (1H, s), 7.45 (1H, s), 7.30 (1H, ddd, J = 8.8, 8.4, 6.6㎐), 6.88 (1H, d, J = 8.4 D, J = 5.8 Hz), 6.78 (1H, d, J = 8.8 Hz), 5.94 (1H, brs) d, J = 5.5, 4.8 Hz), 4.24 (2H, q, J = 7.0 Hz), 3.94 (1H, d, J = 16.1 Hz), 3.91 t, J = 7.0 Hz). LCMS (ESI) m / z 503 [M + H] &lt; ⁺ &gt;.

Reference Example 130

[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

According to Reference Example 128, Step 5, 2-ethynyl-1-fluoro-3-methanesulfanyl-benzene was used instead of 2-ethynyl-1,3-difluorobenzene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.17 (1H, s), 7.62 (1H, s), 7.41 (1H, ddd, J = 8.8, 8.8, 6.2㎐), 7.15 (1H, d, J = (1H, s), 5.56 (1H, br s), 5.10 (1H, s) (1H, d, J = 6.2 Hz), 5.01 (1H, d, J = 6.2 Hz), 4.48 m), 2.55 (3H, s). LCMS (ESI) m / z 505 [M + H] &lt; ⁺ &gt;.

Reference Example 131

Pyrrolo [2,3-d] pyrimidin-7-yl] -3,4-dihydro-pyrrolo [2,3-d] pyrimidin- Roxy-tetrahydrofuran-2-yl] methyl sulfamate

Pyrrolo [2,3-d] pyrimidin-7-yl) -2 (4-methoxybenzyl) , 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methanol

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-3a, 4a, 4a, 3,4-d] [1,3] dioxol-6-yl] methanol (1 g, 2.3 mmol), phenylacetylene (354 mg, 3.5 mmol), bis (triphenylphosphine ) Palladium (II) dichloride (161 mg, 0.23 mmol) and copper iodide (44 mg, 0.23 mmol) were suspended in tetrahydrofuran (10 mL), and then nitrogen substitution was performed. Diisopropylethylamine (0.78 mL, ), And the reaction solution was stirred at 70 ° C for 2 hours. The reaction solution was filtered through celite, washed with chloroform, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (800 mg, 85%) as yellow amorphous.

¹ H-NMR (CDCl ₃ )?: 8.27 (1H, s), 7.51-7.49 (2H, m), 7.39-7.36 (3H, m), 7.27-7.25 J = 10.7 Hz), 5.85-5.72 (2H, br s), 5.72 (1H, d, J = 5.1 Hz), 5.24 4.50 (1H, brs), 4.00-3.96 (1H, m), 3.83-3.76 (1H, m), 1.64 (3H, s), 1.37 (3H, s). LCMS (ESI) m / z 407 [M + H] &lt; ^{+ &}

(Step 2) ((3aR, 4R, 6R, 6aR) -6- (4-Amino-5- (phenylethynyl) -7H- pyrrolo [2,3- d] pyrimidin- , 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl sulfamate

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl (2-methylpiperazin-1- 4-yl) methanol (50 mg, 0.12 mmol) was dissolved in acetonitrile (0.5 mL), and triethylamine (0.084 mL, 0.59 mmol) and sulfamoyl chloride (0.5 M acetonitrile solution, 0.27 mL) was added under an ice bath. After stirring for 40 minutes in an ice bath, the solvent was distilled off, chloroform and aqueous sodium hydrogencarbonate solution were added, and the aqueous layer was extracted with a mixture of chloroform / methanol = 5/1. The organic layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (39 mg, 67%) as yellow amorphous.

_{^{1 H-NMR (CDCl 3)}} δ: 8.29 (1H, s), 7.52-7.49 (2H, m), 7.37-7.36 (3H, m), 7.30 (1H, s), 6.08 (1H, d, J = (2H, brs), 5.35 (1H, dd, J = 6.3, 2.9 Hz), 5.13-5.11 (1H, m), 4.50-4.43 (3H, m), 1.62 ), 1.39 (3H, s). LCMS (ESI) m / z 486 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 131

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl (2-methylpiperazin-1- 4-yl) methyl sulfamate (380 mg, 0.79 mmol) was dissolved in tetrahydrofuran (4 mL), trifluoroacetic acid / water = 4/1 mixed solution (9.5 mL) was added, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off, methanol was added, and the solvent was distilled off. The residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (323 mg, 92%) as a white powder.

¹ H-NMR (CD ₃ OD)?: 8.15 (1H, s), 7.67 (1H, s), 7.55-7.52 (2H, m), 7.39-7.37 = 5.6 Hz), 4.90-4.80 (1H, m), 4.47-4.26 (4 H, m). LCMS (ESI) m / z 446 [M + H] &lt; ⁺ &gt;.

Reference Example 132

[(2R, 3S, 4R, 5R) -5- [4-Amino-5- [2- (2,6- difluorophenyl) ethynyl] pyrrolo [2,3- d] pyrimidin- Yl] -3,4-dihydroxy-tetrahydrofuran-2-yl] methyl sulfamate

According to Reference Example 131, 2-ethynyl-1,3-difluorobenzene was used instead of phenylacetylene to give the title compound.

^{1 H-NMR (DMSO-D} 6) δ: 8.20 (1H, s), 7.97 (1H, s), 7.55-7.50 (1H, m), 7.31-7.25 (2H, m), 6.45-6.37 (2H, (1H, m), 6.13 (1H, d, J = 5.9 Hz), 4.47-4.43 (1H, m), 4.28-4.23 (1H, m), 4.20-4.09 (5H, m). LCMS (ESI) m / z 482 [M + H] &lt; ⁺ &gt;.

Reference Example 133

Pyrrolo [2,3-d] pyrimidin-7-yl] -3H-pyrazolo [3,4-d] pyrimidin- , 4-dihydroxy-tetrahydrofuran-2-yl] methyl sulfamate

According to Reference Example 131, 1-ethynylnaphthalene was used instead of phenylacetylene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.41 (1H, d, J = 8.0㎐), 8.19 (1H, s), 7.94-7.90 (2H, m), 7.86 (1H, s), 7.80 (1H, d, J = 4.0 Hz), 7.69-7.48 (3H, m), 6.29 (1H, d, J = 5.1 Hz), 4.87-4.80 (1H, m), 4.52-4.26 (4H, m). LCMS (ESI) m / z 496 [M + H] &lt; ⁺ &gt;.

Reference Example 134

Pyrrolo [2,3-d] pyrimidin-7-yl] -3-hydroxy-tetrahydrofuran (2R, -2-yl] methyl sulfamate

Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [ (2R, 3S, 5R) -5- (4-Amino-thiophen-2-ylmethyl) The title compound was obtained by using 5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) tetrahydrofuran-3-ol.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.14 (1H, s), 7.67 (1H, s), 7.54-7.52 (2H, m), 7.39-7.36 (3H, m), 6.65 (1H, dd, J Dd, J = 11.0, 3.9 Hz), 4.18 (1H, dt, J = J = 3.2, 3.9 Hz), 2.60 (1H, ddd, J = 13.7, 7.8, 6.1 Hz), 2.39 (1H, ddd, J = 13.7, 6.1, 3.2 Hz). LCMS (ESI) m / z 430 [M + H] &lt; ⁺ &gt;.

Reference Example 135

Pyrrolo [2,3-d] pyrimidin-7-yl] -3-hydroxypyridin-2-yl) -Tetrahydrofuran-2-yl] methyl sulfamate

(Step 1) (2R, 3S, 5R) -5- (4-Amino-5- 7-yl) -2- (hydroxymethyl) tetrahydrofuran-3-ol

Pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) tetrahydrofuran-2-carboxylic acid (100 mg, 0.265 mmol), tetrakis (triphenylphosphine) palladium (0) (15.3 mg, 0.013 mmol), 1-benzyl- 4- (4,4,5,5- , 3,2-dioxaborolan-2-yl) -1H-pyrazole (98 mg, 0.34 mmol) was suspended in a 2M aqueous sodium carbonate solution (0.66 mL) and 1,2-dimethoxyethane (2 mL) Followed by stirring at 100 占 폚 for 3 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then concentrated. The residue was purified by silica gel column chromatography (developing solvent: methanol / chloroform) to obtain the desired product (66 mg, 61%) as a yellow oil.

_{^{1 H-NMR (CDCl 3)}} δ: 8.18 (1H, brs), 7.59 (1H, s), 7.44 (1H, s), 7.38-7.32 (3H, m), 7.27-7.23 (2H, m), 6.90 (1H, s), 6.24 (1H, dd, J = 8.8,5.5 Hz), 5.42-5.38 (1H, s), 3.91 (1H, d, J = 12.5 Hz), 3.75 (1H, d, J = 12.5 Hz), 3.05-2.98 ). LRMS (ESI) m / z 407 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 135

Pyrrolo [2,3-d] pyrimidin-7-yl) -pyridin-2-yl] (53 mg, 0.13 mmol) was dissolved in acetonitrile (1 mL), and then 1-aza-4-azoniabicyclo [2.2.2] hept- Diazabicyclo [2.2.2] octane monohydrochloride (Organic Letters, 2012 10, 2626-2629) (114 mg, 0.26 mmol) in tetrahydrofuran mmol) were added. After the reaction solution was stirred overnight at 40 ° C, trifluoroacetic acid (0.3 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography : Methanol / chloroform) to give the title compound (4.7 mg, 7%) as a milky white solid.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.12 (1H, s), 7.88 (1H, s), 7.69 (1H, s), 7.41 (1H, s), 7.37-7.28 (5H, m), 6.71 ( (2H, brm), 4.18-4.15 (1H, brm), 2.62-2.55 (IH, t, J = 7.0 Hz), 5.39 (2H, s), 4.57-4.52 m), 2.39 - 2.35 (1 H, m). LCMS (ESI) m / z 486 [M + H] &lt; ⁺ &gt;.

Reference Example 136

Pyrrolo [2,3-d] pyrimidin-7-yl] -2,2-dimethyl-lH-pyrrolo [2,3- 3-dihydroxy-cyclopentyl] methyl sulfamate

Pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxypiperazin-1 -yl) ((3aR, 4R, 6R, 6aS) -6- (4-Amino-5-iodo-7H- pyrrolo [2,3- d] pyrimidin- Yl) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol was used to yield the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.10 (1H, s), 7.85 (1H, s), 7.66 (1H, s), 7.37-7.21 (6H, m), 5.39 (2H, s), 5.07- Dd, J = 5.7, 3.5 Hz), 2.48-2.34 (1H, d, J = (2 H, m), 1.82-1.76 (1 H, m). LCMS (ESI) m / z 500 [M + H] &lt; ⁺ &gt;.

Reference Example 137

[(2R, 3S, 5R) -5- [4-Amino-5- [1 - [(3,4-dimethylphenyl) methyl] pyrazol-4-yl] pyrrolo [2,3- d] pyrimidine -7-yl] -3-hydroxy-tetrahydrofuran-2-yl] methyl sulfamate

(Step 1) Synthesis of 1- (3,4-dimethylbenzyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) synthesis

Pyrazole (1.0 g, 5.2 mmol), cesium carbonate (2.18 g, 6.7 mmol, ) And 3,4-dimethylbenzyl chloride (0.98 mL, 6.7 mmol) were suspended in acetonitrile (10 mL), and the mixture was stirred overnight at room temperature. The solid was filtered off with celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (developing solvent: ethyl acetate / hexane) to give the title compound (1.29 g, 80%) as a pale yellow oil.

_{^{1 H-NMR (CDCl 3)}} δ: 7.80 (1H, s), 7.63 (1H, s), 7.14-6.97 (3H, m), 5.21 (2H, s), 2.25 (3H, s), 2.25 (3H , s), 1.29 (12H, s). LRMS (ESI) m / z 313 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 137

According to the same manner as in Reference Example 135, using 1- (3 (trifluoromethyl) phenyl) -1H-pyrazole instead of 1-benzyl-4- (4,4,5,5- , 4-dimethylbenzyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.12 (1H, s), 7.83 (1H, s), 7.66 (1H, s), 7.39 (1H, s), 7.11 (1H, d, J = 7.8㎐) , 7.09 (1H, s), 7.02 (1H, d, J = 7.8 Hz), 6.70 (1H, dd, J = 7.9, 6.2 Hz), 5.29 (2H, s), 4.57-4.52 (2H, m), 4.16 (1H, m), 3.60 (1H, dd, J = 14.1, 7.1 Hz), 2.62-2.55 (1H, m), 2.40-2.34 s), 2.23 (3H, s). LCMS (ESI) m / z 514 [M + H] &lt; ⁺ &gt;.

Reference Example 138

[(1R, 2S, 4R) -4- [4-Amino-5- [1 - [(3,4-dimethylphenyl) methyl] pyrazol-4-yl] pyrrolo [2,3- d] pyrimidine -7-yl] -2-hydroxy-cyclopentyl] methyl sulfamate

(Step 1) (1S, 2R, 4R) -4- (4-Amino-5-iodo-7H-pyrrolo [2,3- d] pyrimidin- Synthesis of cyclopentanol

(3aR, 4R, 6R, 6aS) -6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] (1S, 2R, 4R) -4-amino-2- (hydroxymethyl) cyclopentanol was used in place of diethanol-4-dioxol-

^{1 H-NMR (DMSO-D} 6) δ: 8.06 (1H, s), 7.54 (1H, s), 6.64 (2H, brs), 5.23-5.14 (1H, m), 4.73 (1H, brs), 4.61 (1H, br s), 4.01 (1H, m), 3.48-3.44 (1H, m), 3.41-3.36 (1H, m), 2.23-2.16 -1.85 (2H, m), 1.58-1.50 (1H, m). LCMS (ESI) m / z 375 [M + H] &lt; ^{+ &}

(Step 2) Reference Example Synthesis of Compound 138

Pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxypiperazin-1 -yl) Methyl) tetrahydrofuran-3-ol and 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- Pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) cyclopentanol, By using 1- (3,4-dimethylbenzyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- pyrazole, Compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.10 (1H, s), 7.79 (1H, s), 7.64 (1H, s), 7.26 (1H, s), 7.10 (1H, d, J = 7.8㎐) , 7.09 (1H, s), 7.02 (1H, d, J = 7.8 Hz), 5.39-5.31 (1H, m), 5.29 (2H, s), 4.30-4.20 (3H, m), 2.53-2.46 m), 2.38-2.15 (3H, m), 2.24 (3H, s), 2.23 (3H, s), 1.87-1.79 (1H, m). LCMS (ESI) m / z 512 [M + H] &lt; ⁺ &gt;.

Reference Example 139

Pyrrolo [2,3-d] pyrimidin-7-yl] - (4-methylpiperidin-l- 3-hydroxy-tetrahydrofuran-2-yl] methyl sulfamate

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole instead of 1-benzyl-4- , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (o-tolyl) thiazole, the title compound was obtained.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.07 (1H, s), 8.04 (1H, s), 7.92 (1H, s), 7.67 (1H, d, J = 7.3㎐), 7.42-7.36 (2H, m), 7.34-7.30 (1H, m), 6.75 (1H, t, J = 7.0 Hz), 4.62-4.59 (1H, m), 4.39 (1H, dd, J = (dd, J = 11.0, 3.2 Hz), 4.22 (1H, dd, J = 6.1, 3.2 Hz), 2.59-2.56 (1H, m), 2.56 (3H, s), 2.46-2.41 (1H, LCMS (ESI) m / z 503 [M + H] &lt; ⁺ &gt;.

Reference Example 140

[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- Ethylsulfonyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

(Step 1) Synthesis of tert-butyl N - ((3aR, 4R, 6R, 6aR) -6- (4- 3,4-d] [l, 3] dioxol-4-yl) methyl) sulfamoylcarbamoyl] -2-methyl-pyrrolo [2,3- d] pyrimidin- Synthesis of Bamate

pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyl-lH-pyrrolo [2,3- 4-yl) methyl) sulfamoylcarbamate (39 mg, 0.064 mmol), ethyl (2-ethynyl-3-fluoro (4.5 mg, 0.0064 mmol), copper iodide (1.2 mg, 0.0064 mmol) and diisopropylethylamine (0.022 mmol) were added to a solution of 2- mL, 0.13 mmol) was suspended in tetrahydrofuran (1 mL). The reaction solution was stirred at 50 캜 for 3 hours and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: methanol / chloroform) to give the title compound (28 mg, 66% .

¹ H-NMR (CDCl ₃ )?: 9.15 (1H, d, J = 8.1 Hz), 8.52 (1H, s), 7.31 J = 8.1 Hz), 6.91 (1H, t, J = 8.1 Hz), 6.74-6.59 (2H, brm), 5.68 (1H, d, J = 4.8 Hz) D, J = 6.2 Hz), 4.51 (1H, d, J = 2.2 Hz), 3.72-3.66 (1H, m), 3.60 , 3.02 (3H, q, J = 7.3 Hz), 1.61 (3H, s), 1.45 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.35 (3H, s).

(Step 2) Reference Example Synthesis of Compound 140

ethynyl) -7H-pyrrolo [2,3-c] pyridin-7-ylmethyl) - N- ((3aR, 4R, 6R, 6aR) 2,3-d] pyrimidin-7-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4- yl) methyl) sulfamoylcarbamate 55 Oxazine (102 mg, 0.166 mmol) was added to 1,4-dioxane (0.5 mL) and water (0.5 mL) under ice-cooling, under stirring and stirring. After the reaction solution was stirred at room temperature for 3 hours, the reaction solution was partitioned between ethyl acetate and water, and the organic layer was extracted. After the solvent was distilled off, acetonitrile (0.5 mL), water (0.1 mL) and trifluoroacetic acid (0.5 mL) were added successively to the residue, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (developing solvent: methanol / chloroform) to give the title compound (20 mg) as a pale yellow solid.

^{1 H-NMR (DMSO-D} 6) δ: 8.16 (1H, s), 8.04 (1H, s), 7.82 (2H, d, J = 8.1㎐), 7.77 (2H, t, J = 8.1㎐), (1H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 7.7, 4.8 Hz), 6.58 (1H, m, J = 6.2 Hz), 5.22 (1H, brs), 4.62-4.58 (1H, m), 4.09-4.07 = 7.3 Hz), 3.22-3.17 (1H, m), 3.14-3.06 (1H, m), 1.14 (3H, t, J = 7.3 Hz). LCMS (ESI) m / z 555 [M + H] &lt; ⁺ &gt;.

Reference Example 141

Ethynyl] -7 - [(1R, 2S, 3R, 4R) -2,3-dihydroxy-4- [(Sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine

(Step 1) (5- (Benzyloxy) -2-iodophenyl) (methyl) sulfane

According to the procedure of Reference Example 76, Step 1, 4-iodo-3- (methylsulfanyl) phenol was used instead of 2-bromopyrimidin-5-ol to give the title compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.63 (1H, d, J = 8.6㎐), 7.43-7.34 (5H, m), 6.74 (1H, d, J = 2.9㎐), 6.51 (1H, dd, J = 8.6, 2.8 Hz), 5.06 (2H, s), 3.63 (3H, s). LCMS (ESI) m / z 356 [M + H] &lt; ^{+ &}

(Step 2) Synthesis of (5- (benzyloxy) -2-ethynylphenyl) (methyl) sulfane

(5-benzyloxy) -2-iodophenyl) (methyl) sulfane was used instead of 5- (benzyloxy) -2-bromopyrimidine in accordance with Referential Example 76, Step 2, Compound.

_{^{1 H-NMR (CDCl 3)}} δ: 7.41-7.34 (6H, m), 6.76 (1H, d, J = 2.3㎐), 6.69 (1H, dd, J = 8.4, 2.3㎐), 5.08 (2H, s ), 3.39 (1H, s), 2.45 (3H, s). LCMS (ESI) m / z 255 [M + H] &lt; ^{+ &}

(Step 3) Reference Example Synthesis of Compound 141

According to Reference Example 140, (5- (benzyloxy) -2-ethynylphenyl) (methyl) sulfane was used in place of ethyl (2-ethynyl-3-fluorophenyl) sulfene to give the title compound.

_{^{1 H-NMR (CD 3 OD}} ) δ: 8.20 (1H, s), 7.82 (1H, s), 7.73 (1H, d, J = 8.4㎐), 7.67 (1H, d, J = 2.8㎐), 7.47 (2H, d, J = 6.8 Hz), 7.42-7.32 (4H, m), 5.23 (2H, s), 5.05-4.95 (1H, m), 4.43-4.39 m), 3.30 (3H, s), 3.27-3.12 (2H, m), 2.50-2.42 (1H, m), 2.32-2.28 (1H, m), 1.87-1.79 (1H, m). LCMS (ESI) m / z 627 [M + H].

Reference Example 142

[(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoylamino) methyl] cyclopentyl] -5- [2- -6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine

Pyrrolo [2,3-d] pyrimidin-7 (2S) -7-methoxyquinazolin- Tert-butyl N - (((3aR, 5a) -2,3-dimethyl-tetrahydrofuro [3,4- d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate Pyrrolo [2,3-d] pyrimidin-7-yl) -2,2-dimethyltetrahydro-3aH-cyclopenta [b] thiophene- [d] [1,3] dioxol-4-yl) methyl) sulfamoylcarbamate, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.13 (1H, s), 7.99 (1H, s), 7.81 (1H, d, J = 8.1㎐), 7.76 (1H, t, J = 8.1㎐), (2H, s), 4.89 (2H, d, J = 7.0 Hz), 4.67 (1H, d, J = (1H, m), 3.49 (2H, q, J = 7.3 Hz), 3.10 (1H, M), 1.14 (3H, t, &lt; RTI ID = 0.0 &gt; J = 7.3 Hz). LCMS (ESI) m / z 553 [M + H] &lt; ⁺ &gt;.

Reference Example 143

Ethyl-7 - [(2R, 4S, 5R) -4-hydroxy-5 - [(sulfamoylamino) ) Methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine

Pyrrolo [2,3-d] pyrimidin-7 (2S) -7-methoxyquinazolin- Butyl] -N- [[(2R, 3S) -7- (2-methylpiperazin- 3-hydroxy-tetrahydrofuran-2-yl] methylsulfamoyl) -2-methylsulfamoyl] -2,3-dihydro- ] Carbamate, the title compound was obtained.

^{1 H-NMR (DMSO-D} 6) δ: 8.18 (1H, s), 8.03 (1H, s), 7.87-7.83 (1H, m), 7.80-7.75 (1H, m), 7.73-7.68 (1H, d, J = 8.7, 5.7 Hz), 4.37 (1H, brs), 3.97 (1H, dt, J = = 2.0, 4.6 Hz), 3.50 (2H, q, J = 7.4 Hz), 3.20-3.14 (1H, m), 3.12-3.05 (1H, m), 2.71-2.62 1H, m), 1.15 (3H, t, J = 7.4 Hz). LCMS (ESI) m / z 539 [M + H] &lt; ⁺ &gt;.

Comparative Example

(1S) -1- indanyl] -7 - [(1R) -3? -Hydroxy-4? - (sulfamoyloxymethyl) cyclopentyl] -7H-1-indolecarboxamide was synthesized in accordance with the method described in Patent Document 1, Pyrrolo [2,3-d] pyrimidin-4-amine (MLN4924).

The structural formulas of the compound of the present example are shown in the following table.

Test Example 1 Nedd8 addition inhibitory activity

The purified NAE (complex of APPBP1 and UBA3) solution was prepared as follows. The human APPBP1 gene (NCBI Reference Sequences Accession No. NM_003905) region corresponding to the first amino acid to the 534 amino acid of the human APPBP1 protein (NCBI Reference Sequences registration number NP_003896, total length 534 amino acids) was inserted into pBacPAK9 (manufactured by Clontech) To construct the plasmid pBacPAK9-APPBP1 expressing the APPBP1 full-length protein with His tag and TEV protease recognition sequence. Next, by inserting the region of the human UBA3 gene (NCBI Reference Sequences Accession No. NM_003968) corresponding to the first amino acid to the 463 amino acid of the human UBA3 protein (NCBI Reference Sequences Accession No. NP_003959, total length 463 amino acids) into pBacPAK9, UBA3 full- Lt; RTI ID = 0.0 &gt; pBacPAK9-UBA3 &lt; / RTI &gt; pBacPAK9-APPBP1 or pBacPAK9-UBA3 and BacPAK6 DNA were co-transfected into insect cells (Sf9, made by Clontech), and a recombinant baculovirus having APPBP1 gene or UBA3 gene was prepared. APPBP1 gene recombinant baculovirus and UBA3 gene recombinant baculovirus were mixed and infected with Sf9 cells. Baculovirus-infected Sf9 cells were shake cultured in Grace's Insect Medium (manufactured by GIBCO) at 28 ° C for 72 hours, and the recovered cells were suspended in a lysis buffer (50 mM Tris-HCl, 200 mM NaCl, 10% Glycerol (pH 7.4)) and ultrasonically disrupted. The crushed cell solution was centrifuged (40,000 xg for 30 minutes), and the supernatant was used as crude extract. The crude extract was fractionated by a HisTrap HP column (manufactured by GE Healthcare) and a TALON Superflow column (manufactured by Clontech), followed by addition of TEV protease, and the His tag cleavage reaction was carried out overnight at 4 ° C. This solution was subjected to TALON Superflow column chromatography, and non-adsorbed fractions were recovered. This fraction was applied to a HiLoad 16/60 Superdex 75 prep grade column equilibrated with 50 mM Tris-HCl, 200 mM NaCl, 10% Glycerol (pH 7.4) and fractionated. The fraction containing the APPBP1 / UBA3 complex was concentrated to give a purified NAE solution. The above purification was carried out at 4 캜. The purified NAE solution was stored at -80 ° C until use.

The purified GST-UBC12 solution was prepared as follows. The region of the human UBC12 gene (NCBI Reference Sequences Accession No. NM_003969) corresponding to the first amino acid to the 183 amino acid of the human UBC12 protein (NCBI Reference Sequences Accession No. NP_003960, total length of 183 amino acids) was substituted with pGEX-4T-2 (GE Healthcare) To construct a plasmid pGEX-UBC12 expressing the UBC12 full-length protein having a GST tag at the N-th termini. pGEX-UBC12 was introduced into Escherichia coli (BL21 (DE3), manufactured by Stratagene), and 37 mg of isopropyl-beta-D-thiogalactopyranoside (manufactured by Sigma-Aldrich) Deg.] C for 2 hours, and the recovered Escherichia coli was suspended in PBS and ultrasonically disrupted. The crushed cell solution was centrifuged (40,000 × g, 5 minutes), and the supernatant was used as crude extract. Glutathione Sepharose 4B carrier (GE Healthcare) was added to the crude extract and eluted with 50 mM Tris-HCl (pH 7.9), 150 mM NaCl and 10 mM reduced glutathione solution, and then eluted with 50 mM HEPES (pH 7.5) And dialyzed with a 0.05% BSA solution to obtain a purified GST-UBC12 solution. The purified GST-UBC12 solution was divided and stored at -80 ° C. until use.

The Nedd8 addition inhibitory activity was measured by an Alpha Screen analyzer. The purified NAE solution and the GST-UBC12 solution were each diluted with assay buffer (50 mM HEPES (pH 7.5), 5 mM MgCl ₂ , 1 mM DTT, 0.05% BSA) and 384 well plates , Manufactured by CORNING). After reacting at room temperature for 30 minutes, a solution of ATP and Biotin-Nedd8 (manufactured by Bosto Biochem) diluted with Assay buffer was added and reacted for 90 minutes.

Detection mix (50 mM HEPES (pH 7.5), 0.05% BSA, 0.04 mg / mL anti-GST Acceptor beads, 0.04 mg / mL streptavidin donor beads) (# 6760603M, manufactured by PerkinElmer) was added to each well of the equal volume of the reaction solution. After reacting for 1 hour at room temperature in a dark place, the fluorescence intensity was measured with a multi-label plate reader EnVision (manufactured by PerkinElmer). (%) Of the neddylation by the compound of Reference Example was determined using the following equation (formula A), using the positive control of the fluorescence signal of the test compound-insoluble group, the fluorescence signal of the test compound and the group of the ATP insoluble group as a negative control . The concentration at which Nedd8 addition was inhibited to 50% of control by addition of each compound (IC50 (μM)) was determined as a relative index of Nedd8 addition inhibitory activity.

(%) = 100- (T-B) / (C-B) x 100 (Formula A)

T: Signal of the well to which the test compound is added

C: Signal of the well to which the test compound was not added

B: Signals of the wells to which the test compounds and ATP were not added

The results are shown in Table 16 below.

From these results, the compound of Reference Example showed very good Nedd8 addition inhibitory activity as compared with Comparative Example.

Test Example 2 Inhibition of cell proliferation 1

Cell tether-by quantifying the ATP which by glow ^TM (CellTiter-Glo ^™) luminescent cell viability test (Luminescent Cell Viability Assay) (# G7573, manufactured by Promega whether or claim), derived from the viable cells, cell proliferation of the test compounds And the inhibition was judged. Human acute T lymphocytic leukemia cell line CCRF-CEM (Banpo, Dainippon Seiyaku K.K.) was added to a 96-well plate (# 165305, manufactured by Thermo Scientific Nunc) And seeded in 1,000 / 100 μL medium. After overnight incubation in a 5% CO ₂ incubator at 37 ° C, the test substance was added and further incubated for 72 hours. CellTiter-Glo ^™ Luminescent Cell Viability Assay reagent equivalent to that of the medium was added to each well, stirred for 5 minutes with a shaker under light-shielding conditions, and then allowed to stand at room temperature for about 30 minutes. The amount of luminescence was measured with a microplate reader (EnSpire ^TM Multimode Plate Reader, manufactured by Perkin Elmer Japan Co., Ltd.) and used as an index of the number of living cells in each well. The inhibition rate (%) of cell proliferation by the compound was determined using the amount of light emitted from the untreated control group (control) as a control and using the following formula (formula B). The concentration at which the number of cells was suppressed to 50% of the control by the addition of each compound was determined (IC50 (.mu.M)).

(%) = (C-T) / C 占 100 (Formula B)

T: Amount of light emitted from the well to which the test compound is added

C: Amount of light emitted from the well to which the test substance was not added

The results are shown in Table 17 below.

From these results, these compounds inhibited the proliferation of the human leukemia cell line CCRF-CEM.

Test Example 3 Inhibition of cell proliferation 2

The cell proliferation inhibiting ability of the test compound was determined in the same manner as in Test Example 2, except that the number of cell seeding per cell line, culture plate, and well was changed to the conditions described in Table 18. A 384-well plate (# 3571, manufactured by CORNING) was used as the culture plate.

The results are shown in Table 19 below.

From these results, it can be concluded that these compounds can be used in the treatment of human colon cancer primary HCT116, human pancreatic cancer primary Capan-1, human lung cancer strain A-427, human breast cancer primary MDA-MB-453, human prostate cancer LNCAP.FGC, , Human multiple myeloma U266B1, human skin cancer strain A-431, human acute leukemia cell line MV-4-11 and human sulcus cell type B cell lymphoma main DB.

Example 1: Enhancement of antitumor effect of proteasome inhibitor

(1) Cell proliferation inhibition test

Tumor cell lines and their culture media were those shown in Table 20. All cell lines were obtained from ATCC, Dainippon Sumitomo Chemical Co., Ltd. or HS Research Resources Bank. However, TMD8 was obtained from Tokyo Medical and Dental University (Leuk Res. 2006 Nov; 30 (11): 1385-90.)

The cells were inoculated into a 384-well culture plate (# 3571, manufactured by CORNING) under the conditions shown below at 20 μL / well. Plates seeded cells were cultured in a incubator set to 37 ℃, 5% CO _2. On the next day after sowing, the new pyrrolopyrimidine compound of Reference Example 55 contained 8 kinds of concentrations (including 0 nM) to be isosbestic, 10 kinds of concentrations (0 nM) ), Respectively, were prepared and diluted in RPMI-1640 medium, respectively, and mixed to prepare 80 kinds of compounds having different concentrations. The mixed compound was added to the plate at 5 μL / well, and further cultured at 37 ° C. and 5% CO ₂ for 3 days. Three days later, 25 μL / well of CellTiter-Glo ™ (Promaga) was added and chemiluminescence was measured with a plate reader.

(2) Analysis method

The enhancement of the effect by the combined use of drugs was evaluated according to a method described in a known method (Trends Pharmacol. Sci. 4, 450-454, 1983, Pharmacol Rev. 2006; 58 (3): 621-81).

Specifically, the standardized cell viability by comparison with the control cells, for cells treated with each of the novel pyrrolopyrimidine compounds and the compounds having other antitumor effects, respectively, in a single treatment; T / C (Treatment / Control ratio,%). From the T / C values obtained, the half-life inhibitory concentration (IC50) for each drug was determined by a regression analysis tool of curve fitting using the regression analysis tool XLfit5.3 (IDBS Ltd.).

The ratio (IC50 ratio) of the IC50 of the each agent was determined by the formula (I).

IC50 ratio = [IC50 of a novel pyrrolopyrimidine compound]: [IC50 of a compound having another antitumor effect] (Formula I)

The IC50 ratio obtained by calculation is not equal to the concentration ratio actually used in the experiment when the novel pyrrolopyrimidine compound and the compound having another antitumor effect are mixed. Therefore, it is possible to specify a series which is worthy of the concentration ratio before and after the IC 50 ratio among the concentration ratios of the mixed compounds actually used in the experiment, and calculate the half-life inhibition concentration (ED50) was obtained, and the combination index (CI) in the ED50 was obtained. CI was obtained using the median effect analysis software CalcuSyn 2.0 (CalcuSyn, Inc.), which calculates the median effect method.

The CI obtained was judged to be elevated CI, much more than one antagonist, almost equal CI to one, or much less than one CI, as detailed in Table 21 (Table 21). In the comprehensive evaluation, a determination result in which the enhancing action is weak is adopted among the determination results obtained by treating with the compound mixed at the concentration ratio before and after the IC50 ratio.

(3) Combination with proteasome inhibitor

The cell proliferation inhibition test was conducted with the highest concentration of the novel pyrrolopyrimidine compound of Reference Example Compound 55 shown in Table 22, the compound having other antitumor effect and the highest dose thereof, and the tumor cell line. Table 23 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhanced the antitumor effect when used in combination with the proteasome inhibitor.

Example 2: Enhancement of antitumor effect of tyrosine kinase inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 24, the compound having another antitumor effect, the highest dose thereof, and the tumor cell line. Table 25 shows IC50 ratio, CI, and evaluation results. In the following Examples 2 to 15, the compounds of Reference Example 55 were used as the novel pyrrolopyrimidine compounds in the same manner as in Example 1.

These results indicate that the novel pyrrolopyrimidine compounds can be used in combination with ALK inhibitors, HER family inhibitors (EGFR inhibitors and HER2 inhibitors), CBR-ABL inhibitors, FLT3 inhibitors, VEGFR inhibitors, c-kit inhibitors, When used together, the antitumor effect was enhanced either additively or synergistically.

Example 3: Enhancement of antitumor effect of serine threonine kinase inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 26, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 27 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when it is used in combination with a PI3K inhibitor, an Akt inhibitor, an mTOR inhibitor, and a PLK inhibitor.

Example 4: Enhancement of antitumor effect of PARP inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 28, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 29 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound, when used together with the PARP inhibitor, synergistically enhances the antitumor effect.

Example 5: Enhancement of antitumor effect of steroids

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 30, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 31 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used together with steroids.

Example 6: Enhancement of antitumor effect of immunomodulator

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 32, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 33 shows the IC50 ratio, CI, and evaluation results.

From these results, it has been shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used in combination with an immunomodulator.

Example 7: Enhancement of antitumor effect of exportin-1 inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 34, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 35 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when it is used in combination with the exportin-1 inhibitor.

Example 8: Enhancement of antitumor effect of BTK inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 36, the compound having another antitumor effect, the highest dose thereof, and the tumor cell line. Table 37 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used in combination with the BTK inhibitor.

Example 9: Enhancement of antitumor effect of BCL-2 inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 38, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 39 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used in combination with the BCL-2 inhibitor.

Example 10: Enhancement of antitumor effect of HDAC inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 40, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 41 shows IC50 ratio, CI, and evaluation results.

From these results, it was shown that when the novel pyrrolopyrimidine compound is used together with the HDAC inhibitor, the antitumor effect is increased additively.

Example 11: Enhancement of antitumor effect of metabolic antagonist

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 42, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 43 shows the IC50 ratio, CI, and evaluation results.

From these results, it has been shown that the novel pyrrolopyrimidine compound, when used in combination with a metabolic antagonist, increases the antitumor effect either additively or synergistically.

Example 12: Enhancement of antitumor effect of a platinum preparation (platinum complex)

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 44, the compound having another antitumor effect, the highest dose thereof, and the tumor cell line. Table 45 shows IC50 ratio, CI, and evaluation results.

From these results, it was shown that when the novel pyrrolopyrimidine compound is used together with a platinum preparation (platinum complex), the antitumor effect is synergistically enhanced.

Example 13: Enhancement of antitumor effect of microtubule inhibitor

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 46, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 47 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that when the novel pyrrolopyrimidine compound is used in combination with a microtubule inhibitor, the antitumor effect is increased additively.

Example 14: Enhancing the antitumor effect of an alkylating agent

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 48, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 49 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound, when used in combination with an alkylating agent, increases the antitumor effect either additively or synergistically.

Example 15: Enhancement of antitumor effect of an anthracycline antitumor agent

Similarly to Example 1, the cell proliferation inhibition test was conducted with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 50, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 51 shows the IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used in combination with an anthracycline antitumor agent.

Example 16 Enhancement of Tumor Growth Inhibitory Effect by Combination Treatment with Bortezomib on Mouse Grafted Tumor Cells

Human multiple myeloma (MM) cell line KMS-26 was washed in PBS and suspended at a concentration of 1x10 ⁸ cells / mL in 50% PBS and 50% Martigel basement membrane matrix (# 356237; Corning). The 0.1mL of the cell suspension was implanted subcutaneously in the right chest of a 6-week old CB17 / Icr-Prkdc ^scid / CrlCrlj mice (Nippon Charles River).

The long diameter, short diameter and body weight of the transplanted tumor were measured. The tumor volume (Tumor Volume, TV) was calculated from the following formula (Formula C). The unit of long diameter and short diameter is mm.

TV (㎣) = {(long diameter) x (short diameter) ² } / 2 (formula C)

When the TV reached 100 to 310 kPa, animals were assigned to each group by the stratified random assignment method, and the day was set as Day 1, TV of the day was set to TV1, and body weight was set to BW1. The test was terminated on the 15th day.

The required amount of the test compound was weighed to prepare a solution. (Day 1, 8), or twice a day (Day 1, 4, 8, and 7) was administered intraperitoneally to mice (6 rats / group) 11) intravenously, and bortezomib 1 mg / kg / day intravenously twice a week (Day 1, 4, 8, 11). In the combination treatment group, the reference compound and bortezomib were administered in combination, and evaluation was made for the enhancement of the tumor growth inhibitory effect by the combination treatment. The control group received the administration solvent of Reference Example Compound 55.

Thereafter, the long diameter, short diameter and body weight (BWn) of the tumor on Day n were measured by the same method over time, and the TVn of each individual was calculated. In addition, the relative tumor volume (RTVn) from the TVn of each individual was calculated from the mean RTVn of each drug-administered group by the following equation (D): T / Cn (%) The body weight change rate (BWCn) was calculated by the following formula (formula F) by the following formula (formula E).

RTVn = TVn / TV1 (expression D)

T / Cn (%) = (mean RTV of each drug administration group on day n) / (mean RTV of control group on day n) x 100 (E)

BWCn (%) = (BWn-BW1) / BW1 占 100 (Formula F)

Comparison of RTV15 with the Dunnett test showed that the RTV of the reference compound administration group was significantly lower than that of the control group. Also, RTV15 of the combination treatment group administered with the reference compound 100 mg / kg / day twice a week and bortezomib 1 mg / kg / day twice a week was measured by Aspin-welch t test in RTV 15 of each single drug group , The combined treatment group had a significantly lower value. The change of the RTV at this time is shown in Fig.

Also, the RTV 15 observed in the combination treatment of 100 mg / kg / day of the reference compound once a week and the combination treatment of bortezomib 1 mg / kg / day twice a week was significantly lower than that of the RTV 15 alone . The results are shown in Table 52.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was revealed that the compound of Reference Example enhances the tumor growth inhibitory effect of bortezomib by the combined use.

Example 17 Enhancement of Tumor Growth Inhibitory Effect by Combination Treatment with Gyrteritinib on Mouse Grafted Tumor Cells

Human acute myelogenous leukemia (AML) cell line MV-4-11 was transplanted into BALB / cAJcl-nu / nu mice (Nippon Clea) at 6 weeks of age according to the description of Example 16. When the TV reached 80 to 220 kPa, animals were assigned to each group by the stratified random assignment method, and the day was set as Day 1, TV of the day was set to TV 1, and body weight was set to BW 1. The test was terminated on the 15th day.

Intraperitoneal injection of 50 mg / kg / day, or 100 mg / kg / day (all-in-terms conversion dose) of reference hydrochloride of Reference Example Compound 55 once a day (Day 1, 8) kg / day was orally administered each day. In the combination treatment group, gilateritinib was administered to the compound of Reference Example and evaluation was made for the enhancement of the tumor growth inhibitory effect by the combination treatment with gyrteritinib on human tumors. The control group received the administration solvent of the reference compound.

Comparison of RTV15 with the Dunnett test showed that RTV was significantly lower in the reference compound administration group and gyrteritinib administration group than in the control group. Also, the RTV15 of the combination treatment group administered with 50 mg / kg / day of the reference compound and the daily administration of 3 mg / kg / day of gilateritinib was tested by Aspin-welch t assay for RTV 15 of each single drug group As a result, the combined treatment group had a significantly lower value. The change of the RTV at this time is shown in Fig.

Also, RTV 15 observed in the combination treatment of 100 mg / kg / day (Day 1, 8) administration of the reference compound and 3 mg / kg / day of gilateritinib . The results are shown in Table 53.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was revealed that the compound of Reference Example enhances the tumor growth inhibitory effect of Giltaritinib by the combined use.

Example 18: Enhancement of tumor growth inhibition effect by treatment with doxorubicin in mouse transplantation tumor cells

Human human sarcoma sarcoma cell line SU-CCS-1 was transplanted into BALB / cAJcl-nu / nu mice (Nippon Clea) at 7 weeks of age according to the description of Example 16. When the TV reached 100 to 150 picoseconds, animals were assigned to each group by the stratified random assignment method, and the day was set as Day 0, TV of the day was set to TV0, and body weight was set to BW0. The test was terminated on day 22.

In mice with tumors, 12.5 mg / kg / day, or 25 mg / kg / day (both in terms of free form conversion) of hydrochloride of Reference Example Compound 55 was administered intravenously to Day 1 and 8, and doxorubicin hydrochloride 8 mg / &Lt; / RTI &gt; In the combination treatment group, the compound of Reference Example and doxorubicin hydrochloride were administered, and the enhancement of the tumor growth inhibitory effect by the combination treatment with doxorubicin hydrochloride on human tumors was evaluated. The control group was untreated.

Comparison of RTV22 with the Dunnett test showed that the reference compound and the doxorubicin hydrochloride-treated group had significantly lower RTV values than the control group. Also, RTV22 of the combination treatment group of Day 1, 8 administration of compound 25 mg / kg / day and day 1 administration of doxorubicin hydrochloride 8 mg / kg / day was compared with RTV 22 of each single drug group by Aspin-welch t test However, the combined treatment group had a significantly lower value. The change of the RTV at this time is shown in Fig.

Also, the RTV22 observed in the combination of Day 1, 8 administration of compound 12.5 mg / kg / day and Day 1 administration of doxorubicin 8 mg / kg / day was significantly lower than RTV22 of only one drug group. The results are shown in Table 54.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was revealed that the compound of Reference Example enhances the tumor growth inhibitory effect of doxorubicin by the combined use.

Example 19 Enhancement of Tumor Growth Inhibitory Effect by Combined Treatment with Rituximab on Mouse Grafted Tumor Cells 1

Human dendritic cell type B cell lymphoma (DLBCL) cell line WILL-2 was transplanted into CB17 / Icr-Prkdcscid / CrlCrlj mouse (Nihon Charles River) at 6 weeks of age according to the description of Example 16. When the TV reached 120 to 220 kPa, animals were assigned to each group by the stratified random assignment method, the day was set as Day 1, the TV of the day was set as TV1, and the body weight was set as BW1. The test was terminated on the 15th day.

Intraperitoneal injection of 50 mg / kg / day, or 100 mg / kg / day (all-in-the-pentase converted dose) of the hydrochloride salt of Reference Example Compound 55 once a day (Day 1, 8), and rituximab 10 mg / kg / day was intravenously administered to Day 1. In the combination treatment group, the compound of Reference Example and rituximab were administered, and evaluation was made for the enhancement of the tumor growth inhibitory effect by the combination treatment with rituximab on human tumors. The control group received the administration solvent of the reference compound.

Comparing RTV15 with the Dunnett test, the reference compound and the rituximab group showed a significantly lower RTV value than the control group. Also, the RTV15 of the combined treatment group of the reference compound 50 mg / kg / day and the day 1 administration of rituximab 10 mg / kg / day was administered by Aspin-welch t assay to RTV 15 of each single drug group As a result, the combined treatment group had a significantly lower value. The change of the RTV at this time is shown in Fig.

Also, the RTV 15 observed in the combination treatment of 100 mg / kg / day of the reference compound and 1 mg / kg of Day 1 administration of rituximab was significantly lower than that of the RTV 15 alone . The results are shown in Table 55.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was revealed that the compound of Reference Example enhances the tumor growth inhibitory effect of rituximab by the combined use.

Example 20 Enhancement of Tumor Growth Inhibitory Effect by Combination Treatment with Rituximab on Mouse Grafted Tumor Cells 2

(DLBCL) cell line OCI-LY18 was transplanted into 6-week-old BALB / cAJcl-nu / nu mice (Nippon Clea) according to the description of Example 16. When the TV reached 120 to 210 kPa, animals were assigned to each group by the stratified random assignment method, and the day was set as Day 1, TV of the day was set to TV1, and body weight was set to BW1. The test was terminated on the 15th day.

Intravenous administration of 100 mg / kg / day of the hydrochloride of Reference Example Compound 55 (in terms of the phosgene conversion capacity) to Day 1, 3, 5, or twice a day (Day 1, 4, 8, 11) 10 mg / kg / day was administered intravenously to Day 1. In the combination treatment group, the compound of Reference Example and rituximab were administered, and evaluation was made for the enhancement of the tumor growth inhibitory effect by the combination treatment with rituximab on human tumors. The control group received the administration solvent of the reference compound.

Comparing RTV15 with the Dunnett test, the reference group compound administration group and the rituximab group showed a significantly lower RTV value than the control group. In addition, the RTV15 of the combination treatment group of Day 1, 3 and 5 administration of 100 mg / kg / day of the reference compound and Day 1 administration of 10 mg / kg / day of rituximab was tested by Aspin-welch t test for each single drug group Compared with RTV15, the combined treatment group had a significantly lower value. The change of the RTV at this time is shown in Fig.

Also, the RTV 15 observed in the combination administration of the reference compound 100 mg / kg / day twice a week and the day 1 administration of rituximab 10 mg / kg / day was significantly lower than that of the RTV 15 alone . The results are shown in Table 56.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was found that the compound of Reference Example exhibited moderate enhancement of the tumor growth inhibitory effect of rituximab by the combined use.

Example 21 Enhancement of tumor growth inhibition effect by treatment with azacitidine in mouse transplant tumor cells

The human acute myeloid leukemia (AML) cell line THP-1 was transplanted into BALB / cAJcl-nu / nu mice (Nippon Clea) at 7 weeks of age according to the description of Example 16. When the TV reached 90 to 180., Animals were assigned to each group by the stratified random assignment method, the day was set as Day 1, the TV of the day was set as TV1, and the body weight was set as BW1. The test was terminated on day 22.

Intravenous administration of 12.5 mg / kg / day of the hydrochloride of Reference Example 55 (per dose in terms of phesis) intravenously twice a day (Day 1, 4, 8, 11, 15, 18) / kg / day was administered intraperitoneally twice a week (Day 1, 4, 8, 11, 15, 18). In the combination treatment group, the Reference Example compound and azacytidine were administered, and evaluation was made for the enhancement of the tumor growth inhibitory effect by the combination treatment with azacytidine on human tumors. The control group received the administration solvent of the reference compound.

Comparison of RTV22 with the Dunnett test showed that the twice-weekly dose group of reference compound 12.5 mg / kg / day and the twice-weekly dose of azacytidine 20 mg / kg / day had significantly lower RTV Appeared. In addition, RTV22 of the combined treatment group of these drugs was compared with RTV22 of each single drug group by the Aspin-welch t test, and the combined treatment group had a significantly lower value. The results at this time are shown in FIG. 6 and Table 57.

The average rate of change in body weight in the combination treatment group on the end of the test period was not accompanied by an increase in toxicity as compared with each single drug group.

From these results, it was revealed that the compound of Reference Example increased the tumor growth inhibitory effect of azacytidine to a moderate extent by the combined use.

Example 22: Enhancement of antitumor effect of IAP antagonist

As in Example 1, the cell proliferation inhibition test was performed with the highest concentration of the novel pyrrolopyrimidine compound shown in Table 58, the compound having other antitumor effect, the highest dose thereof, and the tumor cell line. Table 59 shows IC50 ratio, CI, and evaluation results.

From these results, it was shown that the novel pyrrolopyrimidine compound synergistically enhances the antitumor effect when used in combination with an IAP antagonist.

Claims (24)

(A)

[Expression

Is a single bond or a double bond;
X is, -O-, -CH ₂ - or -CH = a;
Y is -NH- or -O-;
R ₁ is hydrogen, fluorine, a hydroxyl group, a cyano group or an amino group;
R ₂ is hydrogen, fluorine, a hydroxyl group, a cyano group or an amino group;
R ₃ is a monocyclic or bicyclic heteroarylene group having at least one hetero atom selected from the group consisting of a vinylene group, an ethynylene group, a C6-C14 arylene group, and N, S, and O;
R ₄ is a bond, a methylene group or a C 3 -C 7 cycloalkylidene group;
R ₅ is one or have a C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O,
R ₆ represents at least one hetero atom selected from the group consisting of halogen, hydroxyl group, cyano group, C1-C6 alkyl group optionally having a phenoxy group, carbamoyl group, C1-C6 alkoxycarbonyl group, Having at least one heteroatom selected from the group consisting of N, S and O, which may have either a monocyclic or bicyclic unsaturated heterocycloalkyl group having an atom, a halogen, a hydroxyl group, a carboxyl group or a C1-C6 alkyl group as a substituent, A monocyclic or bicyclic saturated heterocycloalkyl group,
(C 1 -C 4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent, a halogen atom, a C 3 -C 7 saturated cycloalkyl group and at least one hetero atom selected from the group consisting of N, S and O A C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group or a C1-C6 alkylsulfonyl group which may have a carbamoyl group as a substituent, or a benzyloxy group optionally having a carbamoyl group, Aminosulfonyl group. When R ₆ is a plurality of presence, a plurality of R ₆ may be the same or different and.] Antitumor effect enhancer of a compound having a different anti-tumor effect, which contains a compound represented by the. The positive resist composition according to claim 1, wherein in the general formula (A)
R ₁ is hydrogen, fluorine or hydroxyl;
R ₂ is hydrogen, fluorine or hydroxyl;
R ₃ is an ethynylene group or a monocyclic or bicyclic heteroarylene group having 1 to 4 heteroatoms selected from the group consisting of N, S and O,
Antitumor effect enhancer. The positive resist composition according to claim 1 or 2, wherein in the general formula (A)
R ₁ is a hydroxyl group;
R ₂ is hydrogen or a hydroxyl group;
R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;
R ₅ is optionally having a one or a C3-C7 saturated cycloalkyl groups, one or a C6-C10 unsaturated cycloalkyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O;
R ₆ is halogen; A hydroxyl group; Cyano; A C1-C6 alkyl group which may have a phenoxy group as a substituent; Carbamoyl group; A C1-C6 alkoxycarbonyl group; A monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O; A monocyclic or bicyclic saturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group and a C1-C6 alkyl group; An amino group; A mono or di (C1-C4 alkyl) amino group which may have a hydroxyl group or a phenyl group as a substituent; A C1-6 alkoxy group optionally having a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent; A benzyloxy group which may have a carbamoyl group as a substituent; A C1-C4 alkylthio group; A C1-C4 alkylsulfonyl group; Or aminosulfonyl group (if a plurality of R ₆ is present, a plurality of R ₆ are may be the same or different.), Antitumor effect enhancer. 4. The compound according to any one of claims 1 to 3, wherein in formula (A)
R ₁ is a hydroxyl group;
R ₂ is hydrogen or a hydroxyl group;
R ₃ is a mononuclear heteroarylene group having two ethynylene groups or at least one hetero atom selected from the group consisting of N, S and O;
A C3-C7 saturated cycloalkyl group in which R &lt; ₅ &gt; may have one or more R &lt; _{6 &} gt ;; One or a C6-C10 unsaturated cycloalkyl group which may have a plurality of R _6, or 1 or having at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group;
R ₆ is fluorine; Goat; A hydroxyl group; Cyano; A C1-C6 alkyl group which may have a phenoxy group as a substituent; Carbamoyl group; A C1-C6 alkoxycarbonyl group; A pyridinyl group optionally having at least one substituent selected from the group consisting of a halogen, a hydroxyl group and a C1-C4 alkyl group; Azetidinyl; A hydroxyazetidinyl group; A thiomorpholinyl group; A dioxydothiomorpholinyl group; A methylpiperazinyl group; A hydroxypiperidinyl group; An oxopiperidinyl group; Piperidinyl group; A hydroxypyrrolidinyl group; Oxopyrrolidinyl groups; A pyrrolidinyl group; A carboxypyrrolidinyl group; A fluoropyrrolidinyl group; A morpholinyl group; 9-oxa-3-azabicyclo [3.3.1] nonan-3-yl group; 3-oxa-8-azabicyclo [3.2.1] octan-8-yl group; An amino group; A methylamino group; Ethylamino group; Isopropylamino group; Hydroxyethylamino group; - dimethylamino group; Phenylmethylamino group; A C1-C6 alkoxy group optionally having any one of a halogen, a C3-C7 saturated cycloalkyl group and a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one hetero atom selected from the group consisting of N, S and O as a substituent; A benzyloxy group which may have a carbamoyl group as a substituent; A C1-C4 alkylthio group; A C1-C4 alkylsulfonyl group; Or aminosulfonyl group (if a plurality of R ₆ are present, may be a plurality of R ₆ may be the same or different.),
Antitumor effect enhancer. The positive resist composition according to any one of claims 1 to 4, wherein in the general formula (A)
R ₁ is a hydroxyl group;
R ₂ is a hydroxyl group;
R ₃ is an ethynylene group;
R ₄ is a bond;
R ₅ is one or a C6-C10 which may have a plurality of R ₆ unsaturated cycloalkyl group, or one or heteroaryl of at least one member selected from the group consisting of, N, S and O, which may have a plurality of R ₆ A monocyclic or bicyclic unsaturated heterocycloalkyl group having an atom;
R ₆ is fluorine; Goat; A hydroxyl group; Cyano; Methyl group; A 3-fluoropyrrolidinyl group; A morpholinyl group; A thiomorpholinyl group; A 3-hydroxyazetidinyl group; Azetidinyl; An amino group; N methylamino group; A C1-C6 alkoxy group which may have either of a halogen and a C3-C7 saturated cycloalkyl group as a substituent; Or C1-C4 alkylthio group (if a plurality of R ₆ are present, the plurality of R ₆ are may be the same or different.),
Antitumor effect enhancer. 6. The compound according to any one of claims 1 to 5, wherein in formula (A)
Y is -NH-;
R ₁ is a hydroxyl group;
R ₂ is a hydroxyl group;
R ₃ is an ethynylene group;
R ₄ is a bond;
R ₅ is one or at least a heteroatom in one type of compound selected from the group consisting of, N, S and O, which may have a phenyl group and a naphthyl group, or one or a plurality of R ₆ which may have a plurality of R ₆ Lt; / RTI &gt; is a monocyclic or bicyclic unsaturated heterocycloalkyl group;
R ₆ is fluorine; Methyl group; 3-fluoropyrrolidinyl; 3-hydroxyazetidinyl; Azetidinyl; An amino group; N-methylamino group; A C1-C6 alkoxy group optionally having a cyclopropyl group; Or C1-C4 alkylthio group (if a plurality of R ₆ are present, the plurality of R ₆ are may be the same or different.), Antitumor effect enhancer. 7. The compound according to any one of claims 1 to 6, wherein the compound represented by the general formula (A)
[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoyl) Amino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 4-dihydroxy-4H-pyrrolo [ -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
Yl] phenyl] ethynyl] -7 - [(2R, 3R) -3-fluoropyrrolidin- , 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-4,6-difluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; Ethynyl] -7 - [(2R, 3R, 4S, 5R) -4-amino-5- [2- [2,6-difluoro-4- (3- hydroxyacetidin- -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
Ethynyl] -7 - [(2R, 3R, 4S, 5R) -3, 6-dihydro- 4-dihydroxy-5 - [(sulfamoylamino) methyl] cyclopentyl] pyrrolo [2,3-d] pyrimidine; [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;
[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-fluoro-6-propoxy-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;
[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-oxo-pyrrolo [2,3-d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;
[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - [(sulfamoylamino) methyl] tetrahydrofuran- 2-ethylsulfanyl-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;
Ethyl] -7 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-6-fluoro-phenyl] -5 - [(sulfamoylamino) methyl] tetrahydrofuran-2-yl] pyrrolo [2,3-d] pyrimidine;
Cyclopentyl] -5- [2- (2-fluoro-pyridin-2-ylmethyl) 6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine;
Methyl] cyclopentyl] pyrrolo [2,3-a] pyrimidin-2-one [ -d] pyrimidin-5-yl] ethynyl] -7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;
[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-ethoxy-6-fluoro-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; And
[(1R, 4R, 5S) -4,5-dihydroxy-3 - [(sulfamoylamino) methyl] cyclopent- (2-fluoro-6-methylsulfanyl-phenyl) ethynyl] pyrrolo [2,3-d] pyrimidine; And salts of these compounds. The antitumor effect enhancer according to claim 1, 8. The method according to any one of claims 1 to 7, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome modulator, An antitumor effect enhancer which is one or more selected from metabolic antagonists, platinum antitumor agents, microtubule inhibitors, alkylating agents, and anthracycline antitumor agents. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein said another antitumor effect compound is selected from the group consisting of bortezomib, carfilzomip, dixajomip, alecitinib, clozotinib, apatipinib, erlotinib, Natrium nip, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizarthinib, gilderitinib, sunitinib, legorapenib, levatinate, paropapanib, clonolanib, KPT-330, Eve, Lecithinib, Evelorimus, Rapamycin, AZD5363, MK2206, Eudelalidis, Doublysid, Bolasurit, Olafibris, Prednisolone, dexamethasone, lanalidomide, But are not limited to, rutinib, ABT-199, panovinostat, borinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, femetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, Paclitaxel, trabepetidine, ifosfamide, dacarbazine, toxin Rituximab, azacytidine, and GDC-0152, which is an antitumor effect enhancer. A compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7; And
Compounds having other antitumor effects
Or a pharmaceutically acceptable salt thereof. 11. The method of claim 10, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome modifier, a DNA damaging agent, a metabolic antagonist, , A microtubule inhibitor, an alkylating agent, and an anthracycline antitumor agent. 11. The pharmaceutical composition according to claim 10, wherein the compound having another antitumor effect is selected from the group consisting of bortezomib, carfilzomip, xoxazomib, alecitinib, cryotorib, apatipinib, erlotinib, gefitinib, osmercitinib, lapatinib, ARON380, dasatinib, imatinib, quizarthinib, gilderitinib, sunitinib, legorapenib, levatinib, pazopanib, clonolanib, masitinib, foraminip, losolitinib, , Rapamycin, AZD5363, MK2206, Eudelalis, Dulvalis, Bolasurit, Olafalip, Prednisolone, dexamethasone, lanalidomide, Folandidomide, Thalidomide, KPT-330, Ibutinib, ABT-199, But are not limited to, but are not limited to, monoclonal antibodies, vinocortins, vorinostats, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, femetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, Mead, Dakarbazine, doxorubicin, phosanthrone, ritux Thank, aza City Dean claim 1 and an antitumor or more kinds selected from the GDC-0152. Use of a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 for enhancing the antitumor effect of a compound having another antitumor effect. Use of a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 for the preparation of an antitumor effect enhancer of a compound having another antitumor effect. Use of a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 for the preparation of an antitumor agent in combination with a compound having another antitumor effect. 16. The method according to any one of claims 13 to 15, wherein the compound having another antitumor effect is selected from the group consisting of a kinase inhibitor, an apoptosis inducer, a nuclear receptor receptor modulator, an immunomodulator, an extracellular export signal inhibitor, a proteasome regulator, A metabolic antagonist, a platinum antitumor agent, a microtubule inhibitor, an alkylating agent, and an anthracycline antitumor agent. 16. The pharmaceutical composition according to any one of claims 13 to 15, wherein said another antitumor effect compound is selected from the group consisting of bortezomib, carfilzomip, dixajomip, alecitinib, clozotib, apatipinib, erlotinib, Natrium nip, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizarthinib, gilderitinib, sunitinib, legorapenib, levatinate, paropapanib, clonolanib, KPT-330, Eve, Lecithinib, Evelorimus, Rapamycin, AZD5363, MK2206, Eudelalidis, Doublysid, Bolasurit, Olafibris, Prednisolone, dexamethasone, lanalidomide, But are not limited to, rutinib, ABT-199, panovinostat, borinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, femetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, Paclitaxel, trabepetidine, ifosfamide, dacarbazine, poison Ruby sour piksan anthrone, rituximab, azacytidine and at least use at least selected from a GDC-0152. A compound represented by the general formula (A) or its salt according to any one of claims 1 to 7 as a combination preparation for simultaneous, sequential, or spaced use in the prevention and / or treatment of a tumor, , A compound having a different antitumor effect. A compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 for enhancing the antitumor effect of a compound having another antitumor effect. A pharmaceutical composition for enhancing the antitumor effect of a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 and a compound having another antitumor effect containing a pharmaceutical carrier. An antitumor composition comprising a compound represented by the general formula (A) according to any one of claims 1 to 7 or a salt thereof and a compound having another antitumor effect. A method for treating a tumor comprising administering to a patient a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 and a compound having another antitumor effect. A compound having another antitumor effect, which comprises co-administering a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 and a compound having another antitumor effect to a patient Gt; antitumor effect of &lt; / RTI &gt; A combination of a compound represented by the general formula (A) or a salt thereof according to any one of claims 1 to 7 and a compound having another antitumor effect, for treating a tumor.

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